Novel Polymorphs and Salts

ABSTRACT

The present invention is directed to novel polymorphs and salts of a compound which is an inhibitor of kinase activity.

FIELD OF THE INVENTION

The present invention is directed to novel polymorphs and salts of acompound which is an inhibitor of kinase activity, more specifically acompound which is an inhibitor of the activity or function ofphosphoinositide 3′OH kinase isoform delta (hereinafter PI3Kδ),processes for their preparation, pharmaceutical compositions comprisingthem, and their use in the treatment of various disorders.

BACKGROUND OF THE INVENTION

Cellular membranes represent a large store of second messengers that canbe enlisted in a variety of signal transduction pathways. In relation tofunction and regulation of effector enzymes in phospholipids signalingpathways, class I PI3-kinases (e.g. PI3Kδ) generate second messengersfrom the membrane phospholipid pools. Class I PI3Ks convert the membranephospholipid PI(4,5)P₂ into PI(3,4,5)P₃, which functions as a secondmessenger. PI and PI(4)P are also substrates of PI3K and can bephosphorylated and converted into PI3P and PI(3,4)P₂, respectively. Inaddition, these phosphoinositides can be converted into otherphosphoinositides by 5′-specific and 3′-specific phosphatases. Thus,PI3K enzymatic activity results either directly or indirectly in thegeneration of two 3′-phosphoinositide subtypes which function as secondmessengers in intracellular signal transduction pathways (TrendsBiochem. Sci. 22(7) p. 267-72 (1997) by Vanhaesebroeck et al.; Chem.Rev. 101(8) p. 2365-80 (2001) by Leslie et al; Annu. Rev. Cell Dev.Biol. 17 p. 615-75 (2001) by Katso et al; and Cell. Mol. Life. Sci.59(5) p. 761-79 (2002) by Toker). To date, eight mammalian PI3Ks havebeen identified, divided into three main classes (I, II, and III) on thebasis of sequence homology, structure, binding partners, mode ofactivation, and substrate preference. In vitro, class I PI3Ks canphosphorylate phosphatidylinositol (PI),phosphatidylinositol-4-phosphate (PI4P), andphosphatidylinositol-4,5-bisphosphate (PI(4,5)P₂) to producephosphatidylinositol-3-phosphate (PI3P),phosphatidylinositol-3,4-bisphosphate (PI(3,4)P₂, andphosphatidylinositol-3,4,5-trisphosphate (PI(3,4,5)P₃, respectively.Class II PI3Ks can phosphorylate PI and PI4P. Class II PI3Ks can onlyphosphorylate PI (Vanhaesebroeck et al. (1997), above; Vanhaesebroeck etal. Exp. Cell Res. 253(1) p. 239-54 (1999); and Leslie et al. (2001),above).

Class I PI3K is a heterodimer consisting of a p110 catalytic subunit anda regulatory subunit, and the family is further divided into class Iaand class Ib enzymes on the basis of regulatory partners and mechanismof regulation. Class Ia enzymes consist of three distinct catalyticsubunits (p110α, p110β, and p110δ) that dimerise with five distinctregulatory subunits (p85α, p55α, p50α, p85β, and p55γ), with allcatalytic subunits being able to interact with all regulatory subunitsto form a variety of heterodimers. Class Ia PI3K are generally activatedin response to growth factor-stimulation of receptor tyrosine kinases,via interaction of the regulatory subunit SH2 domains with specificphospho-tyrosine residues of the activated receptor or adaptor proteinssuch as IRS-1. Small GTPases (ras as an example) are also involved inthe activation of PI3K in conjunction with receptor tyrosine kinaseactivation. Both p110α and p110β are constitutively expressed in allcell types, whereas p110δ expression is more restricted to leukocytepopulations and some epithelial cells. In contrast, the single Class Ibenzyme consists of a p110γ catalytic subunit that interacts with a p101regulatory subunit. Furthermore, the Class Ib enzyme is activated inresponse to G-protein coupled receptor (GPCR) systems and its expressionappears to be limited to leukocytes.

As illustrated in Scheme A above, phosphoinositide 3-kinases (PI3Ks)phosphorylate the hydroxyl of the third carbon of the inositol ring. Thephosphorylation of phosphoinositides to generate PtdIns(3,4,5)P₃.PtdIns(3,4)P₂ and PtdIns(3)P, produces second messengers for a varietyof signal transduction pathways, including those essential to cellproliferation, cell differentiation, cell growth, cell size, cellsurvival, apoptosis, adhesion, cell motility, cell migration,chemotaxis, invasion, cytoskeletal rearrangement, cell shape changes,vesicle trafficking and metabolic pathway (Katso et al. (2001), above;and Mol. Med. Today 6(9) p. 347-57 (2000) by Stein et al.).

The activity of PI3-kinases responsible for generating thesephosphorylated signalling products was originally identified as beingassociated with viral oncoproteins and growth factor receptor tyrosinekinases that phosphorylate phosphatidylinositol (PI) and itsphosphorylated derivatives at the 3′-hydroxyl of the inositol ring(Panayotou et al. Trends Cell Biol. 2 p. 358-60 (1992)). However, morerecent biochemical studies have revealed that class I PI3-kinases (e.g.class IA isoform PI3Kδ) are dual-specific kinase enzymes, meaning theydisplay both lipid kinase (phosphorylation of phosphoinositides) as wellas protein kinase activity, which have been shown to be capable ofphosphorylation of other protein as substrates, includingauto-phosphorylation as an intramolecular regulatory mechanism (EMBO J.18(5) p. 1292-302 (1999) by Vanhaesebroeck et al.). Cellular processesin which PI3Ks play an essential role include suppression of apoptosis,reorganization of the actin skeleton, cardiac myocyte growth, glycogensynthase stimulation by insulin, TNFα-mediated neutrophil priming andsuperoxide generation, and leukocyte migration and adhesion toendothelial cells.

PI3-kinase activation, is believed to be involved in a wide range ofcellular responses including cell growth, differentiation, and apoptosis(Parker, Current Biology 5(6) p. 577-79 (1995); and Yao et al. Science267(5206) p. 2003-06 (1995)). PI3-kinase appears to be involved in anumber of aspects of leukocyte activation. A p85-associated PI3-kinasehas been shown to physically associate with the cytoplasmic domain ofCD28, which is an important costimulatory molecule for the activation ofT-cells in response to antigen (Pages et al. Nature 369 p. 327-29(1994); and Rudd, Immunity 4 p. 527-34 (1996)), Activation of T cellsthrough CD28 lowers the threshold for activation by antigen andincreases the magnitude and duration of the proliferative response.These effects are linked to increases in the transcription of a numberof genes including interleukin-2 (IL2), an important T cell growthfactor (Fraser et al. Science 251(4991) p. 313-16 (1991)). PI3Kγ hasbeen identified as a mediator of G beta-gamma-dependent regulation ofJNK activity, and G beta-gamma are subunits of heterotrimeric G proteins(Lopez-llasaca et al. J. Biol. Chem. 273(5) p. 2505-8 (1998)). Recently,(Laffargue at al. Immunity 16(3) p. 441-51 (2002)) it has been describedthat PI3K relays inflammatory signals through various G(i)-coupledreceptors and is central to mast cell function, stimuli in the contextof leukocytes, and immunology including cytokines, chemokines,adenosines, antibodies, integrins, aggregation factors, growth factors,viruses or hormones for example (J. Cell Sci. 114 (Pt 16) p. 2903-10(2001) by Lawlor et al.; Laffargue et at (2002), above; and Curr.Opinion Cell Biol. 14(2) p. 203-13 (2002) by Stephens et al.).

Specific inhibitors against individual members of a family of enzymesprovide invaluable tools for deciphering functions of each enzyme. Twocompounds, LY294002 and wortmannin (hereinafter), have been widely usedas PI3-kinase inhibitors. These compounds are non-specific PI3Kinhibitors, as they do not distinguish among the four members of Class IPI3-kinases. For example, the IC₅₀ values of wortmannin against each ofthe various Class I PI3-kinases are in the range of 1-10 nM. Similarly,the IC₅₀ values for LY294002 against each of these PI3-kinases is about15-20 μM (Fruman et al. Ann. Rev. Biochem. 67 p. 481-507 (1998)), also5-10 microM on CK2 protein kinase and some inhibitory activity onphospholipases. Wortmannin is a fungal metabolite which irreversiblyinhibits PI3K activity by binding covalently to the catalytic domain ofthis enzyme. Inhibition of PI3K activity by wortmannin eliminatessubsequent cellular response to the extracellular factor. For example,neutrophils respond to the chemokine fMet-Leu-Phe (fMLP) by stimulatingPI3K and synthesizing PtdIns (3, 4, 5)P₃. This synthesis correlates withactivation of the respiratory burst involved in neutrophil destructionof invading microorganisms. Treatment of neutrophils with wortmanninprevents the fMLP-induced respiratory burst response (Thelen et al.Proc. Natl. Acad. Sci. USA 91 p. 4960-64 (1994)). Indeed, theseexperiments with wortmannin, as well as other experimental evidence,show that PI3K activity in cells of hematopoietic lineage, particularlyneutrophils, monocytes, and other types of leukocytes, is involved inmany of the non-memory immune response associated with acute and chronicinflammation.

Based on studies using wortmannin, there is evidence that PI3-kinasefunction is also required for some aspects of leukocyte signalingthrough G-protein coupled receptors (Thelen et al. (1994), above).Moreover, it has been shown that wortmannin and LY294002 blockneutrophil migration and superoxide release.

It is now well understood that deregulation of oncogenes and tumoursuppressor genes contributes to the formation of malignant tumours, forexample by way of increased cell growth and proliferation or increasedcell survival. It is also now known that signaling pathways mediated bythe PI3K family have a central role in a number of cell processesincluding proliferation and survival, and deregulation of these pathwaysis a causative factor a wide spectrum of human cancers and otherdiseases (Katso et al. Annual Rev. Cell Dev. Biol. (2001) 17 p. 615-675and Foster et al. J. Cell Science (2003) 116(15) p. 3037-3040). PI3Keffector proteins initiate signalling pathways and networks bytranslocating to the plasma membrane through a conserved PleckstrinHomology (PH) domain, which specifically interacts with PtdIns(3,4,5)P3(Vanhaesebroeck et al. Annu. Rev. Biochem. (2001) 70 p. 535-602). Theeffector proteins signalling through PtdIns(3,4,5)P3 and PH domainsinclude Serine/Threonine (Ser/Thr) kinases, Tyrosine kinases, Rac or ArfGEFs (Guanine nucleotide exchange factors) and Arf GAPs (GTPaseactivating proteins).

In B and T cells PI3Ks have an important role through activation of theTec family of protein tyrosine kinases which include Bruton's tyrosinekinase (BTK) in B cells and Interleukin-2-inducible T-cell kinase (ITK)in T cells. Upon PI3K activation, BTK or ITK translocate to the plasmamembrane where they are subsequently phosphorylated by Src kinases. Oneof the major targets of activated ITK is phospholipase C-gamma (PLCγ1),which hydrolyses PtdIns(4,5)P2 into Ins(3,4,5)P3 and initiates anintracellular increase in calcium levels and diacylglycerol (DAG) whichcan activate Protein Kinases C in activated T cells.

Unlike the Class IA p110α and p110β, p110δ is expressed in a tissuerestricted fashion. Its high expression level in lymphocytes andlymphoid tissues suggests a role in PI3K-mediated signalling in theimmune system. The p110δ kinase dead knock-in mice are also viable andtheir phenotype is restricted to defects in immune signalling (Okkenhauget al. Science (2002) 297 p. 1031-4). These transgenic mice have offeredinsight into the function of PI3Kδ in B-cell and T-cell signalling. Inparticular, p110δ is required for PtdIns(3,4,5)P3 formation downstreamof CD28 and/or T cell Receptor (TCR) signalling. A key effect of PI3Ksignalling downstream of TCR is the activation of Akt, whichphosphorylates anti-apoptotic factors as well as various transcriptionfactors for cytokine production. As a consequence, T cells with inactivep110δ have defects in proliferation and Th1 and Th2 cytokine secretion.Activation of T cells through CD28 lowers the threshold for TCRactivation by antigen and increases the magnitude and duration of theproliferative response. These effects are mediated by thePI3Kδ-dependent increase in the transcription of a number of genesincluding IL2, an important T cell growth factor.

Therefore, PI3K inhibitors are anticipated to provide therapeuticbenefit via its role in modulating T-cell mediated inflammatoryresponses associated to respiratory diseases such as asthma, COPD andcystic fibrosis. In addition, there is indication that T-cell directedtherapies may provide corticosteroid sparing properties (Alexander etal. Lancet (1992) 339 p. 324-8) suggesting that it may provide a usefultherapy either as a standalone or in combination with inhaled or oralglucocorticosteroids in respiratory diseases. A PI3K inhibitor mightalso be used alongside other conventional therapies such as a longacting beta-agonists (LABA) in asthma.

In the vasculature, PI3Kδ is expressed by endothelial cells andparticipates in neutrophil trafficking by modulating the proadhesivestate of these cells in response to TNFalpha (Puri et al. Blood (2004)103(9) p. 3448-58.). A role for PI3Kδ in TNFalpha-induced signalling ofendothelial cells is demonstrated by the pharmacological inhibition ofAkt phosphorylation and PDK1 activity. In addition, PI3Kδ is implicatedin vascular permeability and airway tissue edema through the VEGFpathway (Lee et al. J. Allergy Clin. Immunol. (2006) 118(2) p. 403-9).These observations suggest additional benefits of PI3Kδ inhibition inasthma by the combined reduction of leukocyte extravasation and vascularpermeability associated with asthma. In addition, PI3Kδ activity isrequired for mast cell function both in vitro and in vivo (Ali et al.Nature (2004) 431 p. 1007-11; and Ali et al. J. Immunol. (2008) 180(4)p. 2538-44) further suggesting that PI3K inhibition should be oftherapeutical benefit for allergic indications such asthma, allergicrhinitis and atopic dermatitis.

The role of PI3Kδ in B cell proliferation, antibody secretion, B-cellantigen and IL-4 receptor signalling, B-cell antigen presenting functionis also well established Okkenhaug et al. (2002), above; Al-Alwan et al.J. Immunol. (2007) 178(4) p. 2328-35; and Bilancio et al. Blood (2006)107(2) p. 642-50) and indicates a role in autoimmune diseases such asrheumatoid arthritis or systemic lupus erythematosus. Therefore PI3Kinhibitors may also be of benefit for these indications.

Pharmacological inhibition of PI3Kδ inhibits fMLP-dependent neutrophilchemotaxis on an ICAM coated agarose matrix integrin-dependent biasedsystem (Sadhu et al., J. Immunol. (2003) 170(5) p. 2647-54.). Inhibitionof PI3Kδ regulates neutrophil activation, adhesion and migration withoutaffecting neutrophil mediated phagocytosis and bactericidal activityover Staphylococcus aureus (Sadhu et al. Biochem. Biophys. Res. Commun.(2003) 308(4) p. 764-9). Overall, the data suggest that PI3Kδ inhibitionshould not globally inhibit neutrophil functions required for innateimmune defense. PI3Kδ's role in neutrophils offers further scope fortreating inflammatory diseases involving tissue remodeling such as COPDor rheumatoid arthritis.

In addition, there is also good evidence that class Ia PI3K enzymes alsocontribute to tumourigenesis in a wide variety of human cancers, eitherdirectly or indirectly (Vivanco and Sawyers, Nature Reviews Cancer(2002) 2(7) p. 489-501). For example, inhibition of PI3Kδ may have atherapeutic role for the treatment of malignant haematological disorderssuch as acute myeloid leukaemia (Billottet at al. Oncogene (2006) 25(50)p. 6648-59). Moreover, activating mutations within p110α (PIK3CA gene)have been associated with various other tumors such as those of thecolon and of the breast and lung (Samuels et al. Science (2004)304(5670) p. 554).

It has also been shown that PI3K is involved in the establishment ofcentral sensitization in painful inflammatory conditions (Pezet et al.The J. of Neuroscience (2008) 28 (16) p. 4261-4270).

A wide variety of retroviruses and DNA based viruses activate the PI3Kpathway as a way of preventing host cell death during viral infectionand ultimately exploiting the host cell synthesis machinery for itsreplication (Virology 344(1) p, 131-8 (2006) by Vogt et al.; and Nat.Rev. Microbiol. 6(4) p. 265-75 (2008) by Buchkovich et al.). ThereforePI3K inhibitors may have anti-viral properties in addition to moreestablished oncolytic and anti-inflammatory indications. These antiviraleffects raise interesting prospects in viral induced inflammatoryexacerbations. For example, the common cold human rhinovirus (HRV) isresponsible for more than 50% of respiratory tract infections butcomplications of these infections can be significant in certainpopulations. This is particularly the case in respiratory diseases suchas asthma or chronic obstruction pulmonary disease (COPD). Rhinoviralinfection of epithelial cells leads to a PI3K dependent cytokine andchemokine secretion (J. Biol. Chem. (2005) 280(44) p. 36952 by Newcombet al.). This inflammatory response correlates with worsening ofrespiratory symptoms during infection. Therefore PI3K inhibitors maydampen an exaggerated immune response to an otherwise benign virus. Themajority of HRV strains infect bronchial epithelial cells by initiallybinding to the ICAM-1 receptor. The HRV-ICAM-1 complex is then furtherinternalised by endocytosis and it has been shown that this eventrequires PI3K activity (J. Immunol. (2008) 180(2) p. 870-880 by Lau etal.). Therefore, PI3K inhibitors may also block viral infections byinhibiting viral entry into host cells.

PI3K inhibitors may be useful in reducing other types of respiratoryinfections including the fungal infection aspergillosis (MucosalImmunol. (2010) 3(2) p. 193-205 by Bonifazi et al.). In addition, PI3Kδdeficient mice are more resistant towards infections by the protozoanparasite Leishmania major (J. Immunol. (2009) 183(3) p. 1921-1933 by Liuet al.). Taken with effects on viral infections, these reports suggestthat PI3K inhibitors may be useful for the treatment of a wide varietyof infections.

PI3K inhibition has also been shown to promote regulatory T celldifferentiation (Proc. Natl. Acad. Sci. USA (2008) 105(22) p. 7797-7802by Sauer et al.) suggesting that PI3K inhibitors may serve therapeuticpurposes in auto-immune or allergic indications by inducingimmuno-tolerance towards self antigen or allergen. Recently the PI3Kδisoform has also been linked to smoke induced glucocorticoidinsensitivity (Am. J. Respir. Crit. Care Med. (2009) 179(7) p. 542-548by Marwick et al.). This observation suggests that COPD patients, whichotherwise respond poorly to corticosteroids, may benefit from thecombination of a PI3K inhibitor with a corticosteroid.

PI3K has also been involved in other respiratory conditions such asidiopathic pulmonary fibrosis (IPF). IPF is a fibrotic disease withprogressive decline of lung function and increased mortality due torespiratory failure. In IPF, circulating fibrocytes are directed to thelung via the chemokine receptor CXCR4. PI3K is required for bothsignalling and expression of CXCR4 (Int. J. Biochem. and Cell Biol.(2009) 41 p. 1708-1718 by Mehrad et al). Therefore, by reducing CXCR4expression and blocking its effector function, a PI3K inhibitor shouldinhibit the recruitment of fibrocytes to the lung and consequently slowdown the fibrotic process underlying IPF, a disease with high unmetneed.

Compounds which are PI3-kinase inhibitors may therefore be useful in thetreatment of disorders associated with inappropriate kinase activity, inparticular inappropriate PI3-kinase activity, for example in thetreatment and prevention of disorders mediated by PI3-kinase mechanisms.Such disorders include respiratory diseases including asthma, chronicobstructive pulmonary disease (COPD) and idiopathic pulmonary fibrosis(IPF); viral infections including viral respiratory tract infections andviral exacerbation of respiratory diseases such as asthma and COPD;non-viral respiratory infections including aspergillosis andleishmaniasis; allergic diseases including allergic rhinitis and atopicdermatitis; autoimmune diseases including rheumatoid arthritis andmultiple sclerosis; inflammatory disorders including inflammatory boweldisease; cardiovascular diseases including thrombosis andatherosclerosis; hematologic malignancies; neurodegenerative diseases;pancreatitis; multiorgan failure; kidney diseases; platelet aggregation;cancer; sperm motility; transplantation rejection; graft rejection; lunginjuries; and pain including pain associated with rheumatoid arthritisor osteoarthritis, back pain, general inflammatory pain, post hepaticneuralgia, diabetic neuropathy, inflammatory neuropathic pain (trauma),trigeminal neuralgia and Central pain.

Attempts have been made to prepare compounds which inhibit PI3-kinaseactivity and a number of such compounds have been disclosed in the art.

International patent application PCT/EP2010/055666 (publication numberWO2010/125082) describes compounds having the general formula (I):

and salts thereof.

The examples of international patent application PCT/EP2010/055666(publication number WO2010/125082) describe the preparation ofN-[5-[4-(5-{[(2R,6S)-2,6-dimethyl-4-morpholinyl]methyl}-1,3-oxazol-2-yl)-1H-indazol-6-yl]-2-(methyloxy)-3-pyridinyl]methanesulfonamidewhich may be represented by the formula (II):

hereinafter referred to as “Compound A”.

The present inventors have now found novel polymorphs and salts ofCompound A.

In one embodiment, the salts of Compound A may have properties, forexample solubility, which make them particularly suitable foradministration as a drug, for example as an inhaled drug.

SUMMARY OF THE INVENTION

The invention is directed to novel polymorphs and salts of Compound A.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1 shows an X-ray powder diffraction (XRPD) pattern for the Form(II) polymorph of Compound A.

FIG. 2 shows an XRPD pattern for the Form (III) polymorph of Compound A.

FIG. 3 shows an XRPD pattern for the Form (IV) polymorph of Compound A.

DETAILED DESCRIPTION OF THE INVENTION

In one aspect, the invention is directed to novel polymorphs of CompoundA.

In one embodiment, the invention provides a polymorph (Form II) ofCompound A characterised in that it provides an XRPD pattern comprisingpeaks (°2θ) at about 4.6, about 9.2, about 11.4 and/or about 12.7.

In another embodiment, the invention provides a polymorph (Form II) ofCompound A characterised in that it provides an XRPD pattern comprisingpeaks substantially as set out in Table 1.

In a further embodiment, the invention provides a polymorph (Form II) ofCompound A characterised in that it provides an XRPD patternsubstantially in accordance with FIG. 1.

In one embodiment, the invention provides a polymorph (Form III) ofCompound A characterised in that it provides an XRPD pattern comprisingpeaks (°2θ) at about 6.7, about 8.2, about 9.7 and/or about 12.6.

In another embodiment, the invention provides a polymorph (Form III) ofCompound A characterised in that it provides an XRPD pattern comprisingpeaks substantially as set out in Table 2.

In a further embodiment, the invention provides a polymorph (Form III)of Compound A characterised in that it provides an XRPD patternsubstantially in accordance with FIG. 2.

In one embodiment, the invention provides a polymorph (Form IV) ofCompound A characterised in that it provides an XRPD pattern comprisingpeaks (°2θ) at about 5.8, and/or about 11.6.

In another embodiment, the invention provides a polymorph (Form IV) ofCompound A characterised in that it provides an XRPD pattern comprisingpeaks substantially as set out in Table 3.

In a further embodiment, the invention provides a polymorph (Form IV) ofCompound A characterised in that it provides an XRPD patternsubstantially in accordance with FIG. 3.

When it is indicated herein that there is a peak in an XRPD pattern at agiven value, it is typically meant that the peak is within ±0.2 of thevalue quoted, for example within ±0.1 of the value quoted.

In a further aspect, the invention is directed to novel salts ofCompound A.

In one embodiment, the invention provides a salt of Compound A selectedfrom sodium, tosylate, maleate, hemi pamoate, heminaphthalenedisulfonate, mesitylenesulfonate, hemi biphenyldisulfonate,2-naphthalenesulfonate (napsylate), hemi cinnamate, hemi sebacate, hemipyromellitate and hemi benzenediacrylate.

In another embodiment, the invention provides a salt of Compound Aselected from sodium, tosylate, maleate, hemi pamoate and heminaphthalenedisulfonate.

In another embodiment, the invention provides a salt of Compound Aselected from hemi pamoate, hemi naphthalenedisulfonate,mesitylenesulfonate, hemi biphenyldisulfonate, hemi cinnamate, hemisebacate, hemi pyromellitate and hemi benzenediacrylate.

In another embodiment, the invention provides a salt of Compound Aselected from hemi naphthalenedisulfonate, mesitylenesulfonate, hemibiphenyldisulfonate, hemi cinnamate, hemi sebacate, hemi pyromellitateand hemi benzenediacrylate.

In another embodiment, the invention provides a salt of Compound Aselected from hemi pamoate and hemi naphthalenedisulfonate.

In another embodiment, the invention provides the hemi pamoate salt ofCompound A.

In a further embodiment, the invention provides the heminaphthalenedisulfonate salt of Compound A.

The sodium salt of Compound A is the salt formed betweenN-[5-[4-(5-{[(2R,6S)-2,6-dimethyl-4-morpholinyl]methyl}-1,3-oxazol-2-yl)-1H-indazol-6-yl]-2-(methyoxy)-3-pyridinyl]methanesulfonamideand sodium hydroxide in a stoichiometric ratio of about 1:1. Thetosylate salt of Compound A is the mono tosylate salt formed betweenN-[5-[4-(5-{([(2R,6S)-2,6-dimethyl-4-morpholinyl]methyl}-1,3-oxazol-2-yl)-1H-indazol-6-yl]-2-(methyloxy)-3-pyridinyl]methanesulfonamideand p-toluenesulfonic acid in a stoichiometric ratio of about 1:1. Themaleate salt of Compound A is the mono maleate salt formed betweenN-[5-[4-(5-{[(2R,6S)-2,6-dimethyl-4-morpholinyl]methyl}-1,3-oxazol-2-yl)-1H-indazol-6-yl]-2-(methyloxy)-3-pyridinyl]methanesulfonamideand maleic acid in a stoichiometric ratio of about 1:1. The hemi pamoatesalt of Compound A is the salt formed betweenN-[5-[4-(5-{[(2R,6S)-2,6-dimethyl-4-morpholinyl]methyl}-1,3-oxazol-2-yl)-1H-indazol-6-yl]-2-(methyloxy)-3-pyridinyl]methanesulfonamideand pamoic acid in a stoichiometric ratio of about 2:1. The heminaphthalenedisulfonate salt of Compound A is the salt formed betweenN-[5-[4-(5-{[(2R,6S)-2,6-dimethyl-4-morpholinyl]methyl}-1,3-oxazol-2-yl)-1H-indazol-6-yl]-2-(methyloxy)-3-pyridinyl]methanesulfonamideand naphthalenedisulfonic acid in a stoichiometric ratio of about 2:1.

The mesitylenesulfonate salt of Compound A is the monomesitylenesulfonate salt formed betweenN-[5-[4-(5-{[(2R,6S)-2,6-dimethyl-4-morpholinyl]methyl}-1,3-oxazol-2-yl)-1H-indazol-6-yl]-2-(methyloxy)-3-pyridinyl]methanesulfonamideand mesitylenesulfonic acid dihydrate in a stoichiometric ratio of about1:1. The hemi biphenyldisulfonate salt of Compound A is the salt formedbetweenN-5-[4-(5-{[(2R,6S)-2,6-dimethyl-4-morpholinyl]methyl}-1,3-oxazol-2-yl)-1H-indazol-6-yl]-2-(methyloxy)-3-pyridinyl]methanesulfonamideand biphenyldisulfonic acid in a stoichiometric ratio of about 2:1. The2-naphthalenesulfonate (napsylate) salt of Compound A is the mono2-naphthalenesulfonate (napsylate) salt formed betweenN-[5-[4-(5-{[(2R,6S)-2,6-dimethyl-4-morpholinyl]methyl}-1,3-oxazol-2-yl)-1H-indazol-6-yl]-2-(methyloxy)-3-pyridinyl]methanesulfonamideand 2-naphthalenesulfonic acid in a stoichiometric ratio of about 1:1.The hemi cinnamate salt of Compound A is the salt formed betweenN-[5-[4-(5-{[(2R,6S)-2,6-dimethyl-4-morpholinyl]methyl}-1,3-oxazol-2-yl)-1H-indazol-6-yl]-2-(methyloxy)-3-pyridinyl]methanesulfonamideand trans-cinnamic acid in a stoichiometric ratio of about 2:1. The hemisebacate salt of Compound A is the salt formed betweenN-[5-[4-(5-{[(2R,6S)-2,6-dimethyl-4-morpholinyl]methyl}-1,3-oxazol-2-yl)-1H-indazol-6-yl]-2-(methyloxy)-3-pyridinyl]methanesulfonamideand sebacic acid in a stoichiometric ratio of about 2:1. The hemipyromellitate salt of Compound A is the salt formed betweenN-[5-[4-(5-{[(2R,6S)-2,6-dimethyl-4-morpholinyl]methyl}-1,3-oxazol-2-yl)-1H-indazol-6-yl]-2-(methyloxy)-3-pyridinyl]methanesulfonamideand pyromellitic acid in a stoichiometric ratio of about 2:1. The hemibenzenediacrylate salt of Compound A is the salt formed betweenN-[5-[4-(5-{[(2R,6S)-2,6-dimethyl-4-morpholinyl]methyl}-1,3-oxazol-2-yl)-1H-indazol-6-yl]-2-(methyloxy)-3-pyridinyl]methanesulfonamideand 1,4-benzenediacrylic acid in a stoichiometric ratio of about 2:1.

Also included within the scope of the invention are any solvates, forexample hydrates, complexes and polymorphic forms of the salts of theinvention.

The salts of the invention may exist in crystalline or noncrystallineform, or as a mixture thereof. For salts of the invention that are incrystalline form, the skilled artisan will appreciate thatpharmaceutically acceptable solvates may be formed wherein solventmolecules are incorporated into the crystalline lattice duringcrystallization. Solvates may involve nonaqueous solvents such asethanol, isopropanol, DMSO, acetic acid, ethanolamine, and EtOAc, orthey may involve water as the solvent that is incorporated into thecrystalline lattice. Solvates wherein water is the solvent that isincorporated into the crystalline lattice are typically referred to as“hydrates”. Hydrates include stoichiometric hydrates as well ascompositions containing variable amounts of water. In one embodiment,the invention provides the sodium salt of Compound A as a hydrate.

The invention encompasses the polymorphs and salts of Compound Aisolated in pure form or when admixed with other materials, for exampleother polymorphs, or salts or solvates (inclusive of their polymorphs)of Compound A, or any other material.

Thus, in one aspect there is provided a polymorph or salt of Compound Ain isolated or pure form. “Isolated” or “pure” form refers to a samplein which the polymorph or salt is present in an amount of >75%,particularly >90%, more particularly >95% and even moreparticularly >99% relative to other materials which may be present inthe sample.

TERMS AND DEFINITIONS

As used herein the symbols and conventions used in these processes,schemes and examples are consistent with those used in the contemporaryscientific literature, for example, the Journal of the American ChemicalSociety or the Journal of Biological Chemistry. Standard single-letteror three-letter abbreviations are generally used to designate amino acidresidues, which are assumed to be in the L-configuration unlessotherwise noted. Unless otherwise noted, all starting materials wereobtained from commercial suppliers and used without furtherpurification. Specifically, the following abbreviations may be used inthe examples and throughout the specification:

-   CLR Controlled lab reactor-   DBU 1,8-Diazabicyclo[5.4.0]undec-7-ene-   DCM Dichloromethane-   DMPU 1,3-Dimethyl-3,4,5,6-tetrahydro-2-(1H)-pyrimidinone-   DMSO Dimethylsulfoxide-   Et Ethyl-   EtOAc Ethyl acetate-   g Grams-   h hour(s)-   HPLC High performance liquid chromatography-   IMS Industrial methylated spirits-   IPA Isopropyl alcohol-   LCMS Liquid chromatography mass spectroscopy-   L Litre-   M Molar-   MDAP Mass directed automated preparative HPLC-   Me Methyl-   MeCN Acetonitrile-   MeOH Methanol-   mg Milligrams-   mins Minutes-   ml Millilitres-   mmol Millimoles-   Rt Retention time-   RT Room temperature-   SCX Strong Cation Exchange-   SPE Solid Phase Extraction-   TFA Trifluoroacetic acid-   THF Tetrahydrofuran-   UPLC Ultra high performance liquid chromatography-   UV Ultraviolet

All references to brine are to a saturated aqueous solution of NaCl.

Polymorph and Salt Preparation

The invention is also directed to processes for preparing the polymorphsand salts of Compound A.

In one aspect, the invention provides a process for preparing apolymorph of Compound A which comprises:

-   -   a) stirring Compound A in a suitable solvent such as ethyl        acetate or methanol, at a suitable temperature such as room        temperature, or    -   b) heating a saturated solution of Compound A in a suitable        solvent such as tetrahydrofuran.

In a further aspect, the invention provides a process for preparing asalt of Compound A which comprises contacting Compound A with a suitablebase or acid such as sodium hydroxide, p-toluenesulfonic acid, maleicacid, pamoic acid, mesitylenesulfonic acid dihydrate, biphenyldisulfonicacid, 2-naphthalenesulfonic acid, trans-cinnamic acid, sebacic acid,pyromellitic acid or 1,4-benzenediacrylic acid, in the presence or asuitable solvent such as methanol, tert-butylmethylether,tetrahydrofuran and/or isopropylacetate. In one embodiment, theinvention provides a process for preparing a salt of Compound A whichcomprises contacting Compound A with a suitable base or acid such assodium hydroxide, p-toluenesulfonic acid, maleic acid or pamoic acid, inthe presence or a suitable solvent such as methanol,tert-butylmethylether, tetrahydrofuran and/or isopropylacetate. In afurther embodiment, the invention provides a process for preparing asalt of Compound A which comprises contacting Compound A with a suitableacid such as mesitylenesulfonic acid dihydrate, biphenyldisulfonic acid,2-naphthalenesulfonic acid, trans-cinnamic acid, sebacic acid,pyromellitic acid or 1,4-benzenediacrylic acid, in the presence or asuitable solvent such as methanol, tert-butylmethylether,tetrahydrofuran and/or isopropylacetate.

Compound A may be prepared according to known procedures, such as thosedisclosed in international patent application PCT/EP2010/055666(publication number WO02010/125082) and the Examples section below. Thedisclosure of international patent application PCT/EP2010/055666(publication number WO2010/125082) is incorporated herein by reference.

Methods of Use

The polymorphs and salts of the invention may be useful in the treatmentof disorders wherein the underlying pathology is (at least in part)attributable to inappropriate PI3-kinase activity, such as asthma andchronic obstructive pulmonary disease (COPD). “Inappropriate PI3-kinaseactivity” refers to any PI3-kinase activity that deviates from thenormal PI3-kinase activity expected in a particular patientinappropriate PI3-kinase may take the form of, for instance, an abnormalincrease in activity, or an aberration in the timing and or control ofPI3-kinase activity. Such inappropriate activity may result then, forexample, from overexpression or mutation of the protein kinase leadingto inappropriate or uncontrolled activation. Accordingly, in anotheraspect the invention is directed to methods of treating such disorders.

Such disorders include respiratory diseases including asthma, chronicobstructive pulmonary disease (COPD) and idiopathic pulmonary fibrosis(IPF); viral infections including viral respiratory tract infections andviral exacerbation of respiratory diseases such as asthma and COPD;non-viral respiratory infections including aspergillosis andleishmaniasis; allergic diseases including allergic rhinitis and atopicdermatitis; autoimmune diseases including rheumatoid arthritis andmultiple sclerosis; inflammatory disorders including inflammatory boweldisease; cardiovascular diseases including thrombosis andatherosclerosis; hematologic malignancies; neurodegenerative diseases;pancreatitis; multiorgan failure; kidney diseases; platelet aggregation;cancer; sperm motility; transplantation rejection; graft rejection; lunginjuries; and pain including pain associated with rheumatoid arthritisor osteoarthritis, back pain, general inflammatory pain, post hepaticneuralgia, diabetic neuropathy, inflammatory neuropathic pain (trauma),trigeminal neuralgia and Central pain. In one embodiment, such disordersinclude respiratory diseases including asthma and chronic obstructivepulmonary disease (COPD); allergic diseases including allergic rhinitisand atopic dermatitis; autoimmune diseases including rheumatoidarthritis and multiple sclerosis; inflammatory disorders includinginflammatory bowel disease; cardiovascular diseases including thrombosisand atherosclerosis; hematologic malignancies; neurodegenerativediseases; pancreatitis; multiorgan failure; kidney diseases; plateletaggregation; cancer; sperm motility; transplantation rejection; graftrejection; lung injuries; and pain including pain associated withrheumatoid arthritis or osteoarthritis, back pain, general inflammatorypain, post hepatic neuralgia, diabetic neuropathy, inflammatoryneuropathic pain (trauma), trigeminal neuralgia and Central pain

The methods of treatment of the invention comprise administering a safeand effective amount of a polymorph or salt of the invention to apatient in need thereof. Individual embodiments of the invention includemethods of treating any one of the above-mentioned disorders byadministering a safe and effective amount of a polymorph or salt of theinvention to a patient in need thereof.

As used herein, “treat” in reference to a disorder means: (1) toameliorate or prevent the disorder or one or more of the biologicalmanifestations of the disorder, (2) to interfere with (a) one or morepoints in the biological cascade that leads to or is responsible for thedisorder or (b) one or more of the biological manifestations of thedisorder, (3) to alleviate one or more of the symptoms or effectsassociated with the disorder, or (4) to slow the progression of thedisorder or one or more of the biological manifestations of thedisorder.

As indicated above, “treatment” of a disorder includes prevention of thedisorder. The skilled artisan will appreciate that “prevention” is notan absolute term. In medicine, “prevention” is understood to refer tothe prophylactic administration of a drug to substantially diminish thelikelihood or severity of a disorder or biological manifestationthereof, or to delay the onset of such disorder or biologicalmanifestation thereof.

As used herein, “safe and effective amount” in reference to a polymorphor salt of the invention or other pharmaceutically-active agent means anamount sufficient to treat the patient's condition but low enough toavoid serious side effects (at a reasonable benefit/risk ratio) withinthe scope of sound medical judgment. A safe and effective amount of acompound will vary with the particular compound chosen (e.g. considerthe potency, efficacy, and half-life of the compound); the route ofadministration chosen; the disorder being treated; the severity of thedisorder being treated; the age, size, weight, and physical condition ofthe patient being treated; the medical history of the patient to betreated; the duration of the treatment; the nature of concurrenttherapy; the desired therapeutic effect; and like factors, but cannevertheless be routinely determined by the skilled artisan.

As used herein, “patient” refers to a human (including adults andchildren) or other animal. In one embodiment, “patient” refers to ahuman.

The polymorphs and salts of the invention may be administered by anysuitable route of administration, including both systemic administrationand topical administration. Systemic administration includes oraladministration, parenteral administration, transdermal administrationand rectal administration. Parenteral administration refers to routes ofadministration other than enteral or transdermal, and is typically byinjection or infusion. Parenteral administration includes intravenous,intramuscular, and subcutaneous injection or infusion. Topicaladministration includes application to the skin as well as intraocular,otic, intravaginal, inhaled and intranasal administration. Inhalationrefers to administration into the patient's lungs whether inhaledthrough the mouth or through the nasal passages. In one embodiment, thepolymorphs and salts of the invention may be administered orally. Inanother embodiment, the polymorphs and salts of the invention may beadministered by inhalation. In a further embodiment, the polymorphs andsalts of the invention may be administered intranasally.

The polymorphs and salts of the invention may be administered once oraccording to a dosing regimen wherein a number of doses are administeredat varying intervals of time for a given period of time. For example,doses may be administered one, two, three, or four times per day. In oneembodiment, a dose is administered once per day. In a furtherembodiment, a dose is administered twice per day. Doses may beadministered until the desired therapeutic effect is achieved orindefinitely to maintain the desired therapeutic effect. Suitable dosingregimens for a polymorph or salt of the invention depend on thepharmacokinetic properties of that polymorph or salt, such asabsorption, distribution, and half-life, which can be determined by theskilled artisan. In addition, suitable dosing regimens, including theduration such regimens are administered, for a polymorph or salt of theinvention depend on the disorder being treated, the severity of thedisorder being treated, the age and physical condition of the patientbeing treated, the medical history of the patient to be treated, thenature of concurrent therapy, the desired therapeutic effect, and likefactors within the knowledge and expertise of the skilled artisan. Itwill be further understood by such skilled artisans that suitable dosingregimens may require adjustment given an individual patient's responseto the dosing regimen or over time as individual patient needs change.

Typical daily dosages may vary depending upon the particular route ofadministration chosen. Typical daily dosages for oral administrationrange from 0.001 mg to 50 mg per kg of total body weight, for examplefrom 1 mg to 10 mg per kg of total body weight. For example, dailydosages for oral administration may be from 0.5 mg to 2 g per patient,such as 10 mg to 1 g per patient.

In one aspect, the invention thus provides a method of treating adisorder mediated by inappropriate PI3-kinase activity comprisingadministering a safe and effective amount of a polymorph or salt of theinvention to a patient in need thereof.

In one embodiment, the disorder mediated by inappropriate PI3-kinaseactivity is selected from the group consisting of respiratory diseases(including asthma, chronic obstructive pulmonary disease (COPD) andidiopathic pulmonary fibrosis (IPF)); viral infections (including viralrespiratory tract infections and viral exacerbation of respiratorydiseases such as asthma and COPD); non-viral respiratory infections(including aspergillosis and leishmaniasis); allergic diseases(including allergic rhinitis and atopic dermatitis); autoimmune diseases(including rheumatoid arthritis and multiple sclerosis); inflammatorydisorders (including inflammatory bowel disease); cardiovasculardiseases (including thrombosis and atherosclerosis); hematologicmalignancies; neurodegenerative diseases; pancreatitis; multiorganfailure; kidney diseases; platelet aggregation; cancer; sperm motility;transplantation rejection; graft rejection; lung injuries; and pain(including pain associated with rheumatoid arthritis or osteoarthritis,back pain, general inflammatory pain, post hepatic neuralgia, diabeticneuropathy, inflammatory neuropathic pain (trauma), trigeminal neuralgiaand Central pain).

In one embodiment, the disorder mediated by inappropriate PI3-kinaseactivity is a respiratory disease. In another embodiment, the disordermediated by inappropriate PI3-kinase activity is asthma. In anotherembodiment, the disorder mediated by inappropriate PI3-kinase activityis chronic obstructive pulmonary disease (COPD). In a furtherembodiment, the disorder mediated by inappropriate PI3-kinase activityis idiopathic pulmonary fibrosis (IPF).

In one embodiment, the disorder mediated by inappropriate PI3-kinaseactivity is pain.

In one embodiment, the present invention provides a method of treating arespiratory disease comprising administering a safe and effective amountof a polymorph or salt of the invention to a patient in need thereof.

In another embodiment, the present invention provides a method oftreating asthma comprising administering a safe and effective amount ofa polymorph or salt of the invention to a patient in need thereof.

In one aspect, the invention provides a polymorph or salt of theinvention for use in medical therapy.

In another aspect, the invention provides a polymorph or salt of theinvention for use in the treatment of a disorder mediated byinappropriate PI3-kinase activity.

In a further aspect, the invention provides the use of a polymorph orsalt of the invention in the manufacture of a medicament for use in thetreatment of a disorder mediated by inappropriate PI3-kinase activity.

Compositions

The polymorphs and salts of the invention will normally, but notnecessarily, be formulated into pharmaceutical compositions prior toadministration to a patient.

Accordingly, in one aspect the invention is directed to pharmaceuticalcompositions comprising a polymorph or salt of the invention and one ormore pharmaceutically acceptable excipients.

In another aspect the invention is directed to pharmaceuticalcompositions comprising 0.05 to 1000 mg of a polymorph or salt of theinvention and 0.1 to 2 g of one or more pharmaceutically acceptableexcipients.

In a further aspect the invention is directed to a pharmaceuticalcomposition for the treatment or prophylaxis of a disorder mediated byinappropriate PI3-kinase activity comprising a polymorph or salt of theinvention.

The pharmaceutical compositions of the invention may be prepared andpackaged in bulk form wherein a safe and effective amount of a polymorphor salt of the invention can be extracted and then given to the patientsuch as with powders or syrups. Alternatively, the pharmaceuticalcompositions of the invention may be prepared and packaged in unitdosage form wherein each physically discrete unit contains a polymorphor salt of the invention. When prepared in unit dosage form, thepharmaceutical compositions of the invention typically may contain, forexample, from 0.5 mg to 1 g, or from 1 mg to 700 mg, or from 5 mg to 100mg of a polymorph or salt of the invention.

The pharmaceutical compositions of the invention typically contain onepolymorph or salt of the invention.

As used herein, “pharmaceutically acceptable excipient” means apharmaceutically acceptable material, composition or vehicle involved ingiving form or consistency to the pharmaceutical composition. Eachexcipient must be compatible with the other ingredients of thepharmaceutical composition when commingled such that interactions whichwould substantially reduce the efficacy of the polymorph or salt of theinvention when administered to a patient and interactions which wouldresult in pharmaceutical compositions that are not pharmaceuticallyacceptable are avoided. In addition, each excipient must of course bepharmaceutically-acceptable eg of sufficiently high purity.

The polymorph or salt of the invention and the pharmaceuticallyacceptable excipient or excipients will typically be formulated into adosage form adapted for administration to the patient by the desiredroute of administration. For example, dosage forms include those adaptedfor (1) oral administration such as tablets, capsules, caplets, pills,troches, powders, syrups, elixers, suspensions, solutions, emulsions,sachets, and cachets; (2) parenteral administration such as sterilesolutions, suspensions, and powders for reconstitution; (3) transdermaladministration such as transdermal patches; (4) rectal administrationsuch as suppositories; (5) inhalation such as aerosols, solutions, anddry powders; and (6) topical administration such as creams, ointments,lotions, solutions, pastes, sprays, foams, and gels.

Suitable pharmaceutically acceptable excipients will vary depending uponthe particular dosage form chosen. In addition, suitablepharmaceutically acceptable excipients may be chosen for a particularfunction that they may serve in the composition. For example, certainpharmaceutically acceptable excipients may be chosen for their abilityto facilitate the production of uniform dosage forms. Certainpharmaceutically acceptable excipients may be chosen for their abilityto facilitate the production of stable dosage forms. Certainpharmaceutically acceptable excipients may be chosen for their abilityto facilitate the carrying or transporting of the polymorph or salt ofthe invention once administered to the patient from one organ, orportion of the body, to another organ, or portion of the body. Certainpharmaceutically acceptable excipients may be chosen for their abilityto enhance patient compliance.

Suitable pharmaceutically acceptable excipients include the followingtypes of excipients: diluents, fillers, binders, disintegrants,lubricants, glidants, granulating agents, coating agents, wettingagents, solvents, co-solvents, suspending agents, emulsifiers,sweetners, flavoring agents, flavor masking agents, coloring agents,anticaking agents, hemectants, chelating agents, plasticizers, viscosityincreasing agents, antioxidants, preservatives, stabilizers,surfactants, and buffering agents. The skilled artisan will appreciatethat certain pharmaceutically acceptable excipients may serve more thanone function and may serve alternative functions depending on how muchof the excipient is present in the formulation and what other excipientsare present in the formulation.

Skilled artisans possess the knowledge and skill in the art to enablethem to select suitable pharmaceutically-acceptable excipients inappropriate amounts for use in the invention. In addition, there are anumber of resources that are available to the skilled artisan whichdescribe pharmaceutically acceptable excipients and may be useful inselecting suitable pharmaceutically acceptable excipients. Examplesinclude Remington's Pharmaceutical Sciences (Mack Publishing Company),The Handbook of Pharmaceutical Additives (Gower Publishing Limited), andThe Handbook of Pharmaceutical Excipients (the American PharmaceuticalAssociation and the Pharmaceutical Press).

The pharmaceutical compositions of the invention are prepared usingtechniques and methods known to those skilled in the art. Some of themethods commonly used in the art are described in Remington'sPharmaceutical Sciences (Mack Publishing Company).

Accordingly, in another aspect the invention is directed to process forthe preparation of a pharmaceutical composition comprising a polymorphor salt of the invention and one or more pharmaceutically acceptableexcipients which comprises mixing the ingredients. A pharmaceuticalcomposition comprising a polymorph or salt of the invention may beprepared by, for example, admixture at ambient temperature andatmospheric pressure.

In one embodiment, the polymorph or salt of the invention will beformulated for oral administration. In another embodiment, the polymorphor salt of the invention will be formulated for inhaled administration.In a further embodiment, the polymorph or salt of the invention will beformulated for intranasal administration.

In one aspect, the invention is directed to a solid oral dosage formsuch as a tablet or capsule comprising a safe and effective amount of apolymorph or salt of the invention and a diluent or filler. Suitablediluents and fillers include lactose, sucrose, dextrose, mannitol,sorbitol, starch (e.g. corn starch, potato starch, and pre-gelatinizedstarch), cellulose and its derivatives (e.g. microcrystallinecellulose), calcium sulfate, and dibasic calcium phosphate. The oralsolid dosage form may further comprise a binder. Suitable bindersinclude starch (e.g. corn starch, potato starch, and pre-gelatinizedstarch), gelatin, acacia, sodium alginate, alginic acid, tragacanth,guar gum, povidone, and cellulose and its derivatives (e.g.microcrystalline cellulose). The oral solid dosage form may furthercomprise a disintegrant. Suitable disintegrants include crospovidone,sodium starch glycolate, croscarmelose, alginic acid, and sodiumcarboxymethyl cellulose. The oral solid dosage form may further comprisea lubricant. Suitable lubricants include stearic acid, magnesiumstearate, calcium stearate, and talc.

Where appropriate, dosage unit formulations for oral administration canbe microencapsulated. The composition can also be prepared to prolong orsustain the release as for example by coating or embedding particulatematerial in polymers, wax or the like.

The polymorphs and salts of the invention may also be coupled withsoluble polymers as targetable drug carriers. Such polymers can includepolyvinylpyrrolidone, pyran copolymer,polyhydroxypropylmethacrylamide-phenol,polyhydroxyethylaspartamidephenol, or polyethyleneoxidepolylysinesubstituted with palmitoyl residues. Furthermore, the polymorphs andsalts of the invention may be coupled to a class of biodegradablepolymers useful in achieving controlled release of a drug, for example,polylactic acid, polepsilon caprolactone, polyhydroxy butyric acid,polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates andcross-linked or amphipathic block copolymers of hydrogels.

In another aspect, the invention is directed to a liquid oral dosageform. Oral liquids such as solution, syrups and elixirs can be preparedin dosage unit form so that a given quantity contains a predeterminedamount of a polymorph or salt of the invention. Syrups can be preparedby dissolving the a polymorph or salt of the invention in a suitablyflavored aqueous solution, while elixirs are prepared through the use ofa non-toxic alcoholic vehicle. Suspensions can be formulated bydispersing the polymorph or salt of the invention in a non-toxicvehicle. Solubilizers and emulsifiers such as ethoxylated isostearylalcohols and polyoxy ethylene sorbitol ethers, preservatives, flavoradditive such as peppermint oil or natural sweeteners or saccharin orother artificial sweeteners, and the like can also be added.

In another aspect, the invention is directed to a dosage form adaptedfor administration to a patient by inhalation, for example as a drypowder, an aerosol, a suspension, or a solution composition. In oneembodiment, the invention is directed to a dosage form adapted foradministration to a patient by inhalation as a dry powder. In a furtherembodiment, the invention is directed to a dosage form adapted foradministration to a patient by inhalation via a nebulizer.

Dry powder compositions for delivery to the lung by inhalation typicallycomprise a polymorph or salt of the invention as a finely divided powdertogether with one or more pharmaceutically-acceptable excipients asfinely divided powders. Pharmaceutically-acceptable excipientsparticularly suited for use in dry powders are known to those skilled inthe art and include lactose, starch, mannitol, and mono-, di-, andpolysaccharides. The finely divided powder may be prepared by, forexample, micronisation and milling. Generally, the size-reduced (egmicronised) compound can be defined by a D₅₀ value of about 1 to about10 microns (for example as measured using laser diffraction).

The dry powder may be administered to the patient via a reservoir drypowder inhaler (RDPI) having a reservoir suitable for storing multiple(un-metered doses) of medicament in dry powder form. RDPIs typicallyinclude a means for metering each medicament dose from the reservoir toa delivery position. For example, the metering means may comprise ametering cup, which is movable from a first position where the cup maybe filled with medicament from the reservoir to a second position wherethe metered medicament dose is made available to the patient forinhalation.

Alternatively, the dry powder may be presented in capsules (e.g. gelatinor plastic), cartridges, or blister packs for use in a multi-dose drypowder inhaler (MDPI). MDPIs are inhalers wherein the medicament iscomprised within a multi-dose pack containing (or otherwise carrying)multiple defined doses (or parts thereof) of medicament. When the drypowder is presented as a blister pack, it comprises multiple blistersfor containment of the medicament in dry powder form. The blisters aretypically arranged in regular fashion for ease of release of themedicament therefrom. For example, the blisters may be arranged in agenerally circular fashion on a disc-form blister pack, or the blistersmay be elongate in form, for example comprising a strip or a tape. Eachcapsule, cartridge, or blister may, for example, contain between 20μg-10 mg of the polymorph or salt of the invention.

Aerosols may be formed by suspending or dissolving a polymorph or saltof the invention in a liquified propellant. Suitable propellants includehalocarbons, hydrocarbons, and other liquified gases. Representativepropellants include: trichlorofluoromethane (propellant 11),dichlorofluoromethane (propellant 12), dichlorotetrafluoroethane(propellant 114), tetrafluoroethane (HFA-134a), 1,1-difluoroethane(HFA-152a), difluoromethane (HFA-32), pentafluoroethane (HFA-12),heptafluoropropane (HFA-227a), perfluoropropane, perfluorobutane,perfluoropentane, butane, isobutane, and pentane. Aerosols comprising apolymorph or salt of the invention will typically be administered to apatient via a metered dose inhaler (MDI). Such devices are known tothose skilled in the art.

The aerosol may contain additional pharmaceutically-acceptableexcipients typically used with MDIs such as surfactants, lubricants,cosolvents and other excipients to improve the physical stability of theformulation, to improve valve performance, to improve solubility, or toimprove taste.

There is thus provided as a further aspect of the invention apharmaceutical aerosol formulation comprising a polymorph or salt of theinvention and a fluorocarbon or hydrogen-containing chlorofluorocarbonas propellant, optionally in combination with a surfactant and/or acosolvent.

According to another aspect of the invention, there is provided apharmaceutical aerosol formulation wherein the propellant is selectedfrom 1,1,1,2-tetrafluoroethane, 1,1,1,2,3,3,3-heptafluoro-n-propane andmixtures thereof.

The formulations of the invention may be buffered by the addition ofsuitable buffering agents.

Capsules and cartridges for use in an inhaler or insufflator, of forexample gelatine, may be formulated containing a powder mix forinhalation of a polymorph or salt of the invention and a suitable powderbase such as lactose or starch. Each capsule or cartridge may generallycontain from 20 μg to 10 mg of the polymorph or salt of the invention.Alternatively, the polymorph or salt of the invention may be presentedwithout excipients such as lactose.

The proportion of the active polymorph or salt in the local compositionsaccording to the invention depends on the precise type of formulation tobe prepared but will generally be within the range of from 0.001 to 10%by weight. Generally, for most types of preparations, the proportionused will be within the range of from 0.005 to 1%, for example from 0.01to 0.5%. However, in powders for inhalation or insufflation theproportion used will normally be within the range of from 0.1 to 5%.

Aerosol formulations are preferably arranged so that each metered doseor “puff” of aerosol contains from 20 μg to 10 mg, preferably from 20 μgto 2000 μg, more preferably from about 20 μg to 500 μg of a polymorph orsalt of the invention. Administration may be once daily or several timesdaily, for example 2, 3, 4 or 8 times, giving for example 1, 2 or 3doses each time. The overall daily dose with an aerosol will be withinthe range from 100 μg to 10 mg, preferably from 200 μg to 2000 μg. Theoverall daily dose and the metered dose delivered by capsules andcartridges in an inhaler or insufflator will generally be double thatdelivered with aerosol formulations.

In the case of suspension aerosol formulations, the particle size of theparticulate (e.g., micronised) drug should be such as to permitinhalation of substantially all the drug into the lungs uponadministration of the aerosol formulation and will thus be less than 100microns, desirably less than 20 microns, and in particular in the rangeof from 1 to 10 microns, such as from 1 to 5 microns, more preferablyfrom 2 to 3 microns.

The formulations of the invention may be prepared by dispersal ordissolution of the medicament and a polymorph or salt of the inventionin the selected propellant in an appropriate container, for example,with the aid of sonication or a high-shear mixer. The process isdesirably carried out under controlled humidity conditions.

The chemical and physical stability and the pharmaceutical acceptabilityof the aerosol formulations according to the invention may be determinedby techniques well known to those skilled in the art. Thus, for example,the chemical stability of the components may be determined by HPLCassay, for example, after prolonged storage of the product. Physicalstability data may be gained from other conventional analyticaltechniques such as, for example, by leak testing, by valve deliveryassay (average shot weights per actuation), by dose reproducibilityassay (active ingredient per actuation) and spray distribution analysis.

The stability of the suspension aerosol formulations according to theinvention may be measured by conventional techniques, for example, bymeasuring flocculation size distribution using a back light scatteringinstrument or by measuring particle size distribution by cascadeimpaction or by the “twin impinger” analytical process. As used hereinreference to the “twin impinger” assay means “Determination of thedeposition of the emitted dose in pressurised inhalations usingapparatus A” as defined in British Pharmacopaeia 1988, pages A204-207,Appendix XVII C. Such techniques enable the “respirable fraction” of theaerosol formulations to be calculated. One method used to calculate the“respirable fraction” is by reference to “fine particle fraction” whichis the amount of active ingredient collected in the lower impingementchamber per actuation expressed as a percentage of the total amount ofactive ingredient delivered per actuation using the twin impinger methoddescribed above.

The term “metered dose inhaler” or MDI means a unit comprising a can, asecured cap covering the can and a formulation metering valve situatedin the cap. MDI system includes a suitable channelling device. Suitablechannelling devices comprise for example, a valve actuator and acylindrical or cone-like passage through which medicament may bedelivered from the filled canister via the metering valve to the nose ormouth of a patient such as a mouthpiece actuator.

MDI canisters generally comprise a container capable of withstanding thevapour pressure of the propellant used such as a plastic orplastic-coated glass bottle or preferably a metal can, for example,aluminium or an alloy thereof which may optionally be anodised,lacquer-coated and/or plastic-coated (for example incorporated herein byreference WO96/32099 wherein part or all of the internal surfaces arecoated with one or more fluorocarbon polymers optionally in combinationwith one or more non-fluorocarbon polymers), which container is closedwith a metering valve. The cap may be secured onto the can viaultrasonic welding, screw fitting or crimping. MDIs taught herein may beprepared by methods of the art (e.g. see Byron, above and WO96/32099).Preferably the canister is fitted with a cap assembly, wherein adrug-metering valve is situated in the cap, and said cap is crimped inplace.

In one embodiment of the invention the metallic internal surface of thecan is coated with a fluoropolymer, more preferably blended with anon-fluoropolymer. In another embodiment of the invention the metallicinternal surface of the can is coated with a polymer blend ofpolytetrafluoroethylene (PTFE) and polyethersulfone (PES). In a furtherembodiment of the invention the whole of the metallic internal surfaceof the can is coated with a polymer blend of polytetrafluoroethylene(PTFE) and polyethersulfone (PES).

The metering valves are designed to deliver a metered amount of theformulation per actuation and incorporate a gasket to prevent leakage ofpropellant through the valve. The gasket may comprise any suitableelastomeric material such as, for example, low density polyethylene,chlorobutyl, bromobutyl, EPDM, black and white butadiene-acrylonitrilerubbers, butyl rubber and neoprene. Suitable valves are commerciallyavailable from manufacturers well known in the aerosol industry, forexample, from Valois, France (e.g. DF10, DF30, DF60), Bespak plc, UK(e.g. BK300, BK357) and 3M-Neotechnic Ltd, UK (e.g. Spraymiser™).

In various embodiments, the MDIs may also be used in conjunction withother structures such as, without limitation, overwrap packages forstoring and containing the MDIs, including those described in U.S. Pat.Nos. 6,119,853; 6,179,118; 6,315,112; 6,352,152; 6,390,291; and6,679,374, as well as dose counter units such as, but not limited to,those described in U.S. Pat. Nos. 6,360,739 and 6,431,168.

Conventional bulk manufacturing methods and machinery well known tothose skilled in the art of pharmaceutical aerosol manufacture may beemployed for the preparation of large-scale batches for the commercialproduction of filled canisters. Thus, for example, in one bulkmanufacturing method for preparing suspension aerosol formulations ametering valve is crimped onto an aluminium can to form an emptycanister. The particulate medicament is added to a charge vessel andliquefied propellant together with the optional excipients is pressurefilled through the charge vessel into a manufacturing vessel. The drugsuspension is mixed before recirculation to a filling machine and analiquot of the drug suspension is then filled through the metering valveinto the canister. In one example bulk manufacturing method forpreparing solution aerosol formulations a metering valve is crimped ontoan aluminium can to form an empty canister. The liquefied propellanttogether with the optional excipients and the dissolved medicament ispressure filled through the charge vessel into a manufacturing vessel.

In an alternative process, an aliquot of the liquefied formulation isadded to an open canister under conditions which are sufficiently coldto ensure the formulation does not vaporise, and then a metering valvecrimped onto the canister.

Typically, in batches prepared for pharmaceutical use, each filledcanister is check-weighed, coded with a batch number and packed into atray for storage before release testing.

Suspensions and solutions comprising a polymorph or salt of theinvention may also be administered to a patient via a nebulizer. Thesolvent or suspension agent utilized for nebulization may be anypharmaceutically-acceptable liquid such as water, aqueous saline,alcohols or glycols, e.g., ethanol, isopropylalcohol, glycerol,propylene glycol, polyethylene glycol, etc. or mixtures thereof. Salinesolutions utilize salts which display little or no pharmacologicalactivity after administration. Both organic salts, such as alkali metalor ammonium halogen salts, e.g., sodium chloride, potassium chloride ororganic salts, such as potassium, sodium and ammonium salts or organicacids, e.g., ascorbic acid, citric acid, acetic acid, tartaric acid,etc. may be used for this purpose.

Other pharmaceutically-acceptable excipients may be added to thesuspension or solution. The polymorph or salt of the invention may bestabilized by the addition of an inorganic acid, e.g., hydrochloricacid, nitric acid, sulphuric acid and/or phosphoric acid; an organicacid, e.g., ascorbic acid, citric acid, acetic acid, and tartaric acid,etc., a complexing agent such as EDTA or citric acid and salts thereof;or an antioxidant such as antioxidant such as vitamin E or ascorbicacid. These may be used alone or together to stabilize the polymorph orsalt of the invention. Preservatives may be added such as benzalkoniumchloride or benzoic acid and salts thereof. Surfactant may be addedparticularly to improve the physical stability of suspensions. Theseinclude lecithin, disodium dioctylsulphosuccinate, oleic acid andsorbitan esters.

In a further aspect, the invention is directed to a dosage form adaptedfor intranasal administration.

Formulations for administration to the nose may include pressurisedaerosol formulations and aqueous formulations administered to the noseby pressurised pump. Formulations which are non-pressurised and adaptedto be administered topically to the nasal cavity are of particularinterest. Suitable formulations contain water as the diluent or carrierfor this purpose. Aqueous formulations for administration to the lung ornose may be provided with conventional excipients such as bufferingagents, tonicity modifying agents and the like. Aqueous formulations mayalso be administered to the nose by nebulisation.

The polymorph and salts of the invention may be formulated as a fluidformulation for delivery from a fluid dispenser, for example a fluiddispenser having a dispensing nozzle or dispensing orifice through whicha metered dose of the fluid formulation is dispensed upon theapplication of a user-applied force to a pump mechanism of the fluiddispenser. Such fluid dispensers are generally provided with a reservoirof multiple metered doses of the fluid formulation, the doses beingdispensable upon sequential pump actuations. The dispensing nozzle ororifice may be configured for insertion into the nostrils of the userfor spray dispensing of the fluid formulation into the nasal cavity. Afluid dispenser of the aforementioned type is described and illustratedin WO05/044354, the entire content of which is hereby incorporatedherein by reference. The dispenser has a housing which houses a fluiddischarge device having a compression pump mounted on a container forcontaining a fluid formulation. The housing has at least onefinger-operable side lever which is movable inwardly with respect to thehousing to cam the container upwardly in the housing to cause the pumpto compress and pump a metered dose of the formulation out of a pumpstem through a nasal nozzle of the housing. In one embodiment, the fluiddispenser is of the general type illustrated in FIGS. 30-40 ofWO05/044354.

Pharmaceutical compositions adapted for intranasal administrationwherein the carrier is a solid include a coarse powder having a particlesize for example in the range 20 to 500 microns which is administered byrapid inhalation through the nasal passage from a container of thepowder held close up to the nose. Suitable compositions wherein thecarrier is a liquid, for administration as a nasal spray or as nasaldrops, include aqueous or oil solutions of the polymorph or salt of theinvention.

Pharmaceutical compositions adapted for transdermal administration maybe presented as discrete patches intended to remain in intimate contactwith the epidermis of the patient for a prolonged period of time. Forexample, the active ingredient may be delivered from the patch byiontophoresis as generally described in Pharmaceutical Research, 3(6),318 (1986).

Pharmaceutical compositions adapted for topical administration may beformulated as ointments, creams, suspensions, lotions, powders,solutions, pastes, gels, sprays, aerosols or oils.

Ointments, creams and gels, may, for example, be formulated with anaqueous or oily base with the addition of suitable thickening and/orgelling agent and/or solvents. Such bases may thus, for example, includewater and/or an oil such as liquid paraffin or a vegetable oil such asarachis oil or castor oil, or a solvent such as polyethylene glycol.Thickening agents and gelling agents which may be used according to thenature of the base include soft paraffin, aluminium stearate,cetostearyl alcohol, polyethylene glycols, woolfat, beeswax,carboxypolymethylene and cellulose derivatives, and/or glycerylmonostearate and/or non-ionic emulsifying agents.

Lotions may be formulated with an aqueous or oily base and will ingeneral also contain one or more emulsifying agents, stabilising agents,dispersing agents, suspending agents or thickening agents.

Powders for external application may be formed with the aid of anysuitable powder base, for example, talc, lactose or starch. Drops may beformulated with an aqueous or non-aqueous base also comprising one ormore dispersing agents, solubilising agents, suspending agents orpreservatives.

Topical preparations may be administered by one or more applications perday to the affected area; over skin areas occlusive dressings mayadvantageously be used. Continuous or prolonged delivery may be achievedby an adhesive reservoir system.

For treatments of the eye or other external tissues, for example mouthand skin, the compositions may be applied as a topical ointment orcream. When formulated in an ointment, the polymorph or salt of theinvention may be employed with either a paraffinic or a water-miscibleointment base. Alternatively, the a polymorph or salt of the inventionmay be formulated in a cream with an oil-in-water cream base or awater-in-oil base.

Pharmaceutical compositions adapted for parenteral administrationinclude aqueous and non-aqueous sterile injection solutions which maycontain anti-oxidants, buffers, bacteriostats and solutes which renderthe formulation isotonic with the blood of the intended recipient; andaqueous and non-aqueous sterile suspensions which may include suspendingagents and thickening agents. The compositions may be presented inunit-dose or multi-dose containers, for example sealed ampoules andvials, and may be stored in a freeze-dried (lyophilized) conditionrequiring only the addition of the sterile liquid carrier, for examplewater for injections, immediately prior to use. Extemporaneous injectionsolutions and suspensions may be prepared from sterile powders, granulesand tablets.

The polymorphs and salts and pharmaceutical compositions according tothe invention may be used in combination with or include one or moreother therapeutic agents, for example selected from anti-inflammatoryagents, anticholinergic agents (particularly an M₁/M₂/M₃ receptorantagonist), β₂-adrenoreceptor agonists, antiinfective agents, such asantibiotics or antivirals, or antihistamines. The invention thusprovides, in a further aspect, a combination comprising a polymorph orsalt of the invention together with one or more other therapeuticallyactive agents, for example selected from an anti-inflammatory agent,such as a corticosteroid or an NSAID, an anticholinergic agent, aβ₂-adrenoreceptor agonist, an antiinfective agent, such as an antibioticor an antiviral, or an antihistamine. One embodiment of the inventionencompasses combinations comprising a polymorph or salt of the inventiontogether with a β₂-adrenoreceptor agonist, and/or an anticholinergic,and/or a PDE-4 inhibitor, and/or an antihistamine.

In one embodiment, the invention encompasses a method of treating adisorder mediated by inappropriate PI3-kinase activity comprisingadministering a safe and effective amount of a combination comprising apolymorph or salt of the invention together with one or moretherapeutically active agents.

In a further aspect, the invention provides a combination comprising apolymorph or salt of the invention which is selective for PI3Kδ togetherwith a compound or pharmaceutically acceptable salt thereof which isselective for another PI3-kinase, for example PI3Kγ.

One embodiment of the invention encompasses combinations comprising oneor two other therapeutic agents.

It will be clear to a person skilled in the art that, where appropriate,the other therapeutic ingredient(s) may be used in the form of salts,for example as alkali metal or amine salts or as acid addition salts, orprodrugs, or as esters, for example lower alkyl esters, or as solvates,for example hydrates to optimise the activity and/or stability and/orphysical characteristics, such as solubility, of the therapeuticingredient. It will be clear also that, where appropriate, thetherapeutic ingredients may be used in optically pure form.

In one embodiment, the invention encompasses a combination comprising apolymorph or salt of the invention together with a β₂-adrenoreceptoragonist.

Examples of β₂-adrenoreceptor agonists include salmeterol (which may bea racemate or a single enantiomer such as the R-enantiomer), salbutamol(which may be a racemate or a single enantiomer such as theR-enantiomer), formoterol (which may be a racemate or a singleduastereomer such as the R,R-diastereomer), salmefamol, fenoterolcarmoterol, etanterol, naminterol, clenbuterol, pirbuterol, flerbuterol,reproterol, bambuterol, indacaterol, terbutaline and salts thereof, forexample the xinafoate (1-hydroxy-2-naphthalenecarboxylate) salt ofsalmeterol, the sulphate salt or free base of salbutamol or the fumaratesalt of formoterol. In one embodiment, long-acting β₂-adrenoreceptoragonists, for example, compounds which provide effective bronchodilationfor about 12 hrs or longer, are preferred.

Other β₂-adrenoreceptor agonists include those described in WO02/066422, WO 021070490, WO 02/076933, WO 03/024439, WO 03/072539, WO03/091204, WO 04/016578, WO 2004/022547, WO 2004/037807, WO 2004/037773,WO 2004/037768, WO 2004/039762, WO 2004/039766, WO01/42193 andWO03/042160.

Examples of β₂-adrenoreceptor agonists include:

-   3-(4-{[6-({(2R)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)hexyl]oxy}butyl)benzenesulfonamide;-   3-(3-{[7-({(2R)-2-hydroxy-2-[4-hydroxy-3-hydroxymethyl)phenyl]ethyl}-amino)heptyl]oxy}propyl)benzenesulfonamide;-   4-{(1R)-2-[(6-{2-[(2,6-dichlorobenzyl)oxy]ethoxy}hexyl)amino]-1-hydroxyethyl}-2-(hydroxymethyl)phenol;-   4-{(1R)-2-[(6-{4-[3-(cyclopentylsulfonyl)phenyl]butoxy}hexyl)amino]-1-hydroxyethyl}-2-(hydroxymethyl)phenol;-   N-[2-hydroxyl-5-[(1R)-1-hydroxy-2-[[2-4-[[(2R)-2-hydroxy-2-phenylethyl]amino]phenyl]ethyl]amino]ethyl]phenyl}formamide;-   N-2{2-[4-(3-phenyl-4-methoxyphenyl)aminophenyl]ethyl}-2-hydroxy-2-(8-hydroxy-2(1H)-quinolinon-5-yl)ethylamine;    and-   5-[(R)-2-(2-{4-[4-(2-amino-2-methyl-propoxy)-phenylamino]-phenyl}-ethylamino)-1-hydroxy-ethyl]-8-hydroxy-1H-quinolin-2-one.

The β₂-adrenoreceptor agonist may be in the form of a salt formed with apharmaceutically acceptable acid selected from sulphuric, hydrochloric,fumaric, hydroxynaphthoic (for example 1- or 3-hydroxy-2-naphthoic),cinnamic, substituted cinnamic, triphenylacetic, sulphamic, sulphanilic,naphthaleneacrylic, benzoic, 4-methoxybenzoic, 2- or 4-hydroxybenzoic,4-chlorobenzoic and 4-phenylbenzoic acid.

Suitable anti-inflammatory agents include corticosteroids. Suitablecorticosteroids which may be used in combination with the polymorphs orsalts of the invention are those oral and inhaled corticosteroids andtheir pro-drugs which have anti-inflammatory activity. Examples includemethyl prednisolone, prednisolone, dexamethasone, fluticasonepropionate,6α,9α-difluoro-11β-hydroxy-16α-methyl-17α-[(4-methyl-1,3-thiazole-5-carbonyl)oxy]-3-oxo-androsta-1,4-diene-17β-carbothioicacid S-fluoromethyl ester,6α,9α-difluoro-17α-[(2-furanycarbonyl)oxy]-11β-hydroxy-16α-methyl-3-oxo-androsta-1,4-diene-17β-carbothioicacid S-fluoromethyl ester (fluticasone furoate),6α,9α-difluoro-11β-hydroxy-16α-methyl-3-oxo-17α-propionyloxy-androsta-1,4-diene-17β-carbothioicacid S-(2-oxo-tetrahydro-furan-3S-yl)ester,6α,9α-difluoro-11β-hydroxy-16α-methyl-3-oxo-17α-(2,2,3,3-tetramethycyclopropylcarbonyl)oxy-androsta-1,4-diene-17β-carbothioicacid S-cyanomethyl ester and6α,9α-difluoro-11β-hydroxy-16α-methyl-17α-(1-methycyclopropylcarbonyl)oxy-3-oxo-androsta-1,4-diene-17β-carbothioicacid S-fluoromethyl ester, beclomethasone esters (for example the17-propionate ester or the 17,21-dipropionate ester), budesonide,flunisolide, mometasone esters (for example mometasone furoate),triamcinolone acetonide, rofleponide, ciclesonide(16α,17-[[(R)-cyclohexylmethylene]bis(oxy)]-11β,21-dihydroxy-pregna-1,4-diene-3,20-dione),butixocort propionate, RPR-106541, and ST-126. Preferred corticosteroidsinclude fluticasone propionate,6α,9α-difluoro-11β-hydroxy-16α-methyl-17α-[(4-methyl-1,3-thiazole-5-carbonyl)oxy]-3-oxo-androsta-1,4-diene-17β-carbothioicacid S-fluoromethyl ester,6α,9α-difluoro-17α-[(2-furanylcarbonyl)oxy]-11β-hydroxy-16α-methyl-3-oxo-androsta-1,4-diene-17α-carbothioicacid S-fluoromethyl ester,6α,9α-difluoro-11β-hydroxy-16α-methyl-3-oxo-17α-(2,2,3,3-tetramethycyclopropylcarbonyl)oxy-androsta-1,4-diene-17(3-carbothioicacid S-cyanomethyl ester and6α,9α-difluoro-11β-hydroxy-16α-methyl-7α-(1-methycyclopropylcarbonyl)oxy-3-oxo-androsta-1,4-diene-17β-carbothioicacid S-fluoromethyl ester. In one embodiment the corticosteroid is6α,9α-difluoro-17α-[(2-furanylcarbonyl)oxy]-11β-hydroxy-16α-methyl-3-oxo-androsta-1,4-diene-17β-carbothioicacid S-fluoromethyl ester.

Examples of corticosteroids may include those described inWO2002/088167, WO2002/100879, WO2002/12265, WO02002/12266,WO2005/005451, WO2005/005452, WO2006/072599 and WO2006/072600.

Non-steroidal compounds having glucocorticoid agonism that may possessselectivity for transrepression over transactivation and that may beuseful in combination therapy include those covered in the followingpatents: WO03/082827, WO98/54159, WO4/005229, WO04/009017, WO04/018429,WO03/104195, WO03/082787, WO03/082280, WO03/059899, WO03/101932,WO02/02565, WO01/16128, WO00/66590, WO03/086294, WO04/026248,WO03/061651 and WO31/08277. Further non-steroidal compounds are coveredin: WO2006/000401, WO2006/000398 and WO2006/015870.

Examples of anti-inflammatory agents include non-steroidalanti-inflammatory drugs (NSAID's).

Examples of NSAID's include sodium cromoglycate, nedocromil sodium,phosphodiesterase (PDE) inhibitors (for example, theophylline, PDE4inhibitors or mixed PDE3/PDE4 inhibitors), leukotriene antagonists,inhibitors of leukotriene synthesis (for example montelukast), iNOSinhibitors, tryptase and elastase inhibitors, beta-2 integrinantagonists and adenosine receptor agonists or antagonists (e.g.adenosine 2a agonists), cytokine antagonists (for example chemokineantagonists, such as a CCR3 antagonist) or inhibitors of cytokinesynthesis, or 5-lipoxygenase inhibitors. An iNOS (inducible nitric oxidesynthase inhibitor) is preferably for oral administration. Examples ofiNOS inhibitors include those disclosed in WO93/13055, WO098/30537,WO02/50021, WO95/34534 and WO99/62875. Examples of CCR3 inhibitorsinclude those disclosed in WO02/26722.

In one embodiment, the invention provides the use of the polymorphs andsalts of the invention in combination with a phosphodiesterase 4 (PDE4)inhibitor, especially in the case of a formulation adapted forinhalation. The PDE4-specific inhibitor useful in this aspect of theinvention may be any compound that is known to inhibit the PDE4 enzymeor which is discovered to act as a PDE4 inhibitor, and which are onlyPDE4 inhibitors, not compounds which inhibit other members of the PDEfamily, such as PDE3 and PDE5, as well as PDE4.

Compounds includecis-4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexan-1-carboxylicacid,2-carbomethoxy-4-cyano-4-(3-cyclopropylmethoxy-4-difluoromethoxyphenyl)cyclohexan-1-oneandcis-[4-cyano-4-(3-cyclopropylmethoxy-4-difluoromethoxyphenyl)cyclohexan-1-ol].Also,cis-4-cyano-4-[3-(cyclopentyloxy)-4-methoxyphenyl]cyclohexane-1-carboxylicacid (also known as cilomilast) and its salts, esters, pro-drugs orphysical forms, which is described in U.S. Pat. No. 5,552,438 issued 3Sep., 1996; this patent and the compounds it discloses are incorporatedherein in full by reference.

Other compounds include AWD-12-281 from Elbion (Hofgen, N. et al. 15thEFMC Int Symp Med Chem (September 6-10, Edinburgh) 1998, Abst P. 98; CASreference No. 247584020-9); a 9-benzyladenine derivative nominatedNCS-613 (INSERM); D-4418 from Chiroscience and Schering-Plough; abenzodiazepine PDE4 inhibitor identified as CI-1018 (PD-168787) andattributed to Pfizer; a benzodioxole derivative disclosed by Kyowa Hakkoin WO99/16766; K-34 from Kyowa Hakko; V-11294A from Napp (Landells, L.J. et al. Eur Resp J [Annu Cong Eur Resp Soc (September 19-23, Geneva)1998]1998, 12 (Suppl. 28): Abst P2393); roflumilast (CAS reference No162401-32-3) and a pthalazinone (WO99/47505, the disclosure of which ishereby incorporated by reference) from Byk-Gulden; Pumafentrine,(−)-p-[(4aR*,10bS*)-9-ethoxy-1,2,3,4,4a,10b-hexahydro-8-methoxy-2-methylbenzo[c][1,6]naphthyridin-6-yl]-N,N-diisopropylbenzamidewhich is a mixed PDE3/PDE4 inhibitor which has been prepared andpublished on by Byk-Gulden, now Altana; arofylline under development byAlmirall-Prodesfarma; VM554/UM565 from Vernalis; or T-440 (TanabeSeiyaku; Fuji, K. et al, J Pharmacol Exp Ther, 1998, 284(1): 162), andT2585.

Further compounds are disclosed in the published international patentapplication WO04/024728 (Glaxo Group Ltd), WO04/056823 (Glaxo Group Ltd)and WO04/103998 (Glaxo Group Ltd) (e.g. Example 399 or 544 disclosedtherein). Further compounds are also disclosed in WO2005/058892,WO2005/090348, WO2005/090353, and WO2005/090354, all in the name ofGlaxo Group Limited.

Examples of anticholinergic agents are those compounds that act asantagonists at the muscarinic receptors, in particular those compoundswhich are antagonists of the M₁ or M₃ receptors, dual antagonists of theM₁/M₃ or M₂/M₃, receptors or pan-antagonists of the M₁/M₂/M₃ receptors.Exemplary compounds for administration via inhalation includeipratropium (for example, as the bromide, CAS 22254-24-6, sold under thename Atrovent), oxitropium (for example, as the bromide, CAS 30286-75-0)and tiotropium (for example, as the bromide, CAS 136310-93-5, sold underthe name Spiriva). Also of interest are revatropate (for example, as thehydrobromide, CAS 262586-79-8) and LAS-34273 which is disclosed inWO01/04118. Exemplary compounds for oral administration includepirenzepine (CAS 28797-61-7), darifenacin (CAS 133099-04-4, or CAS133099-07-7 for the hydrobromide sold under the name Enablex),oxybutynin (CAS 5633-20-5, sold under the name Ditropan), terodiline(CAS 15793-40-5), tolterodine (CAS 124937-51-5, or CAS 124937-52-6 forthe tartrate, sold under the name Detrol), otilonium (for example, asthe bromide, CAS 26095-59-0, sold under the name Spasmomen), trospiumchloride (CAS 10405-02-4) and solifenacin (CAS 242478-37-1, or CAS242478-38-2 for the succinate also known as YM-905 and sold under thename Vesicare).

Additional compounds are disclosed in WO 2005/037280, WO 2005/046586 andWO 20051104745, incorporated herein by reference. The presentcombinations include, but are not limited to:

-   (3-endo)-3-(2,2-di-2-thienylethenyl)-8,8-dimethyl-8-dimethyl-8-azoniabicyclo[3.2.1]octane    iodide;-   (3-endo)-3-(2-cyano-2,2-diphenylethyl)-8,8-dimethyl-8-azoniabicyclo[3.2.1]octane    bromide;-   4-[hydroxy(diphenyl)methyl]-1-2-[(phenylmethyl)oxy]ethyl)-1-azoniabicyclo[2.2.2]octane    bromide; and-   (1R,5S)-3-(2-cyano-2,2-diphenylethyl)-8-methyl-8-{2-[(phenylmethyl)oxy]ethyl}-8-azoniabicyclo[3.2.1]octane    bromide.

Other anticholinergic agents include compounds which are disclosed inU.S. patent application 60/487,981 including, for example:

-   (3-endo)-3-(2,2-di-2-thienylethenyl)-8,8-dimethyl-8-azoniabicyclo[3.2.1]octane    bromide;-   (3-endo)-3-(2,2-diphenylethenyl)-8,8-dimethyl-8-azoniabicyclo[3.2.1]octane    bromide;-   (3-endo)-3-(2,2-diphenylethenyl)-8,8-dimethyl-8-azoniabicyclo[3.2.1]octane    4-methylbenzenesulfonate;-   (3-endo)-8,8-dimethyl-3-[2-phenyl-2-(2-thienyl)ethenyl]-8-azoniabicyclo[3.2.1]octane    bromide; and/or-   (3-endo)-8,8-dimethyl-3-[2-phenyl-2-(2-pyridinyl)ethenyl]-8-azoniabicyclo[3.2.1]octane    bromide.

Further anticholinergic agents include compounds which are disclosed inU.S. patent application 60/511,009 including, for example:

-   (endo)-3-(2-methoxy-2,2-di-thiophen-2-yl-ethyl)-8,8-dimethyl-8-azonia-bicyclo[3.2.1]octane    iodide;-   3-((endo)-8-methyl-8-aza-bicyclo[3.2.1]oct-3-yl)-2,2-diphenyl-propionitrile;-   (endo)-8-methyl-3-(2,2,2-triphenyl-ethyl)-8-aza-bicyclo[3.2.1]octane;-   3-((endo)-8-methyl-8-aza-bicyclo[3.2.1]oct-3-yl)-2,2-diphenyl-propionamide;-   3-((endo)-8-methyl-8-aza-bicyclo[3.2.1]oct-3-yl)-2,2-diphenyl-propionic    acid;-   (endo)-3-(2-cyano-2,2-diphenyl-ethyl)-8,8-dimethyl-8-azonia-bicyclo[3.2.1]octane    iodide;-   (endo)-3-(2-cyano-2,2-diphenyl-ethyl)-8,8-dimethyl-8-azonia-bicyclo[3.2.1]octane    bromide;-   3-((endo)-8-methyl-8-aza-bicyclo[3.2.1]oct-3-yl)-2,2-diphenyl-propan-1-ol;-   N-benzyl-3-((endo)-8-methyl-8-aza-bicyclo[3.2.1]oct-3-yl)-2,2-diphenyl-propionamide;-   (endo)-3-(2-carbamoyl-2,2-diphenyl-ethyl)-8,8-dimethyl-8-azonia-bicyclo[3.2.1]octane    iodide;-   1-benzyl-3-[3-((endo)-8-methyl-8-aza-bicyclo[3.2.1]oct-3-yl)-2,2-diphenyl-propyl]-urea;-   1-ethyl-3-[3-((endo)-8-methyl-8-aza-bicyclo[3.2.1]oct-3-yl)-2,2-diphenyl-propyl]-urea;-   N-[3-((endo)-8-methyl-8-aza-bicyclo[3.2.1]oct-3-yl)-2,2-diphenyl-propyl]-acetamide;-   N-[3-((endo)-8-methyl-8-aza-bicyclo[3.2.1]oct-3-yl)-2,2-diphenyl-propyl]-benzamide;-   3-((endo)-8-methyl-8-aza-bicyclo[3.2.1]oct-3-yl)-2,2-di-thiophen-2-yl-propionitrile;-   (endo)-3-(2-cyano-2,2-di-thiophen-2-yl-ethyl)-8,8-dimethyl-8-azonia-bicyclo[3.2.1]octane    iodide;-   N-[3-((endo)-8-methyl-8-aza-bicyclo[3.2.1]oct-3-yl)-2,2-diphenyl-propyl]-benzenesulfonamide;-   [3-((endo)-8-methyl-8-aza-bicyclo[3.2.1]oct-3-yl)-2,2-diphenyl-propyl]-urea;-   N-[3-((endo)-8-methyl-8-aza-bicyclo[3.2.1]oct-3-yl)-2,2-diphenyl-propyl]-methanesulfonamide;    and/or-   (endo)-3-{2,2-diphenyl-3-[(1-phenyl-methanoyl)-amino]-propyl}-8,8-dimethyl-8-azonia-bicyclo[3.2.1]octane    bromide.

Further compounds include:

-   (endo)-3-(2-methoxy-2,2-di-thiophen-2-yl-ethyl)-8,8-dimethyl-8-azonia-bicyclo[3.2.1]octane    iodide;-   (endo)-3-(2-cyano-2,2-diphenyl-ethyl)-8,8-dimethyl-8-azonia-bicyclo[3.2.1]octane    iodide;-   (endo)-3-(2-cyano-2,2-diphenyl-ethyl)-8,8-dimethyl-8-azonia-bicyclo[3.2.1]octane    bromide;-   (endo)-3-(2-carbamoyl-2,2-diphenyl-ethyl)-8,8-dimethyl-8-azonia-bicyclo[3.2.1]octane    iodide;-   (endo)-3-(2-cyano-2,2-di-thiophen-2-yl-ethyl)-8,8-dimethyl-8-azonia-bicyclo[3.2.1]octane    iodide; and/or-   (endo)-3-{2,2-diphenyl-3-[(1-phenyl-methanoyl)-amino]-propyl}-8,8-dimethyl-8-azonia-bicyclo[3.2.1]octane    bromide.

In one embodiment the invention provides a combination comprising apolymorph or salt of the invention together with an H1 antagonist.Examples of H1 antagonists include, without limitation, amelexanox,astemizole, azatadine, azelastine, acrivastine, brompheniramine,cetirizine, levocetirizine, efletirizine, chlorpheniramine, clemastine,cyclizine, carebastine, cyproheptadine, carbinoxamine,descarboethoxyloratadine, doxylamine, dimethindene, ebastine,epinastine, efletirizine, fexofenadine, hydroxyzine, ketotifen,loratadine, levocabastine, mizolastine, mequitazine, mianserin,noberastine, meclizine, norastemizole, olopatadine, picumast,pyrilamine, promethazine, terfenadine, tripelennamine, temelastine,trimeprazine and triprolidine, particularly cetirizine, levocetirizine,efletirizine and fexofenadine. In a further embodiment the inventionprovides a combination comprising a polymorph or salt of the inventiontogether with an H3 antagonist (and/or inverse agonist). Examples of H3antagonists include, for example, those compounds disclosed inWO2004/035556 and in WO2006/045416. Other histamine receptor antagonistswhich may be used in combination with the polymorphs and salts of thepresent invention include antagonists (and/or inverse agonists) of theH4 receptor, for example, the compounds disclosed in Jablonowski et al.,J. Med. Chem., 46:3957-3960 (2003).

The invention thus provides, in a further aspect, a combinationcomprising a polymorph or salt of the invention together with a PDE4inhibitor.

The invention thus provides, in a further aspect, a combinationcomprising a polymorph or salt of the invention together withβ₂-adrenoreceptor agonist.

The invention thus provides, in a further aspect, a combinationcomprising a polymorph or salt of the invention together with acorticosteroid.

The invention thus provides, in a further aspect, a combinationcomprising a polymorph or salt of the invention together with anon-steroidal GR agonist.

The invention thus provides, in a further aspect, a combinationcomprising a polymorph or salt of the invention together with ananticholinergic.

The invention thus provides, in a further aspect, a combinationcomprising a polymorph or salt of the invention together with anantihistamine.

The invention thus provides, in a further aspect, a combinationcomprising a polymorph or salt of the invention together with a PDE4inhibitor and a β₂-adrenoreceptor agonist.

The invention thus provides, in a further aspect, a combinationcomprising a polymorph or salt of the invention together with ananticholinergic and a PDE-4 inhibitor.

The combinations referred to above may conveniently be presented for usein the form of a pharmaceutical composition and thus pharmaceuticalcompositions comprising a combination as defined above together with apharmaceutically acceptable diluent or carrier represent a furtheraspect of the invention.

The individual components of such combinations may be administeredeither sequentially or simultaneously in separate or combinedpharmaceutical formulations. In one embodiment, the individualcomponents will be administered simultaneously in a combinedpharmaceutical formulation. Appropriate doses of known therapeuticagents will readily be appreciated by those skilled in the art.

The invention thus provides, in a further aspect, a pharmaceuticalcomposition comprising a combination of a polymorph or salt of theinvention together with another therapeutically active agent.

The invention thus provides, in a further aspect, a pharmaceuticalcomposition comprising a combination of a polymorph or salt of theinvention together with a PDE4 inhibitor.

The invention thus provides, in a further aspect, a pharmaceuticalcomposition comprising a combination of a polymorph or salt of theinvention together with a β₂-adrenoreceptor agonist.

The invention thus provides, in a further aspect, a pharmaceuticalcomposition comprising a combination of a polymorph or salt of theinvention together with a corticosteroid.

The invention thus provides, in a further aspect, a pharmaceuticalcomposition comprising a combination of a polymorph or salt of theinvention together with a non-steroidal GR agonist.

The invention thus provides, in a further aspect, a pharmaceuticalcomposition comprising a combination of a polymorph or salt of theinvention together with an anticholinergic.

The invention thus provides, in a further aspect, a pharmaceuticalcomposition comprising a combination of a polymorph or salt of theinvention together with an antihistamine.

The invention thus provides, in a further aspect, a pharmaceuticalcomposition comprising a combination of a polymorph or salt of theinvention together with a PDE4 inhibitor and a β₂-adrenoreceptoragonist.

The invention thus provides, in a further aspect, a pharmaceuticalcomposition comprising a combination of a polymorph or salt of theinvention together with an anticholinergic and a PDE4 inhibitor.

The invention will now be illustrated by way of the followingnon-limiting examples.

EXAMPLES

The following examples illustrate the invention. These examples are notintended to limit the scope of the present invention, but rather toprovide guidance to the skilled artisan to prepare and use thepolymorphs, salts, compositions, and methods of the present invention.While particular embodiments of the present invention are described, theskilled artisan will appreciate that various changes and modificationscan be made without departing from the spirit and scope of theinvention.

When the name of a commercial supplier is given after the name of acompound or a reagent, for instance “compound X (Aldrich)” or “compoundX/Aldrich”, this means that compound X is obtainable from a commercialsupplier, such as the commercial supplier named. If not referencedherein the compound or reagent can be purchased from a standard suppliersuch as Sigma Aldrich, Lancaster, Fluorochem, TCI etc.

The names of the compounds have been obtained using a compound namingprogramme which matches structure to name (e.g. ACD/Name Batch v 9.0).

General Experimental Details

Liquid Chromatography Mass Spectroscopy (LCMS) Methods

LCMS analysis has been carried out using one of the methods listedbelow.

Method A:

LCMS instrumentation consists of the following:

Column: Acquity UPLC BEH C₁₈ 1.7 μm 2.1 mm×50 mm. Column oven set to 40degrees centigrade

Solvent A: Water 0.1% Formic Acid+10 mM Ammonium Acetate Solvent B:MeCN:Water 95:5+0.05% Formic Acid

Injection volume: 0.5 μlinjection technique: Partial loop overfillUV detection: 220 to 330 nmUV sampling rate: 40 points per secondMS scan range: 100 to 1000 amuMS scanning rate: 0.2 second scan with a 0.1 second inter scan delayMS scan function: Electrospray with pos neg switchingCycle time: 2 minutes and 30 seconds

Gradient:

Time Flow ml/min % A % B 0 1 97 3 0.1 1 97 3 1.4 1 0 100 1.9 1 0 100 2 197 3

Method B:

The HPLC analysis was conducted on a Sunfire C18 column (30 mm×4.6 mmi.d. 3.5 μm packing diameter) at 30 degrees centigrade.

Solvent A=0.1% v/v solution of Formic Acid in Water.Solvent B=0.1% v/v solution of Formic Acid in Acetonitrile.

The gradient employed was:

Time (min) Flow Rate (ml/min) % A % B 0 3 97 3 0.1 3 97 3 4.2 3 0 1004.8 3 0 100 4.9 3 97 3 5.0 3 97 3

The UV detection was an averaged signal from wavelength of 210 nm to 350nm and mass spectra were recorded on a mass spectrometer usingalternate-scan positive and negative mode electrospray ionization.

Method C:

The HPLC analysis was conducted on a Phenomenex Luma C18(2) (50 mm×2 mmi.d. 3 μm packing diameter, or validated equivalent) at 40 degreescentigrade.

Solvent A=0.05% v/v solution of TFA in Water.Solvent B=0.05% v/v solution of TFA in Acetonitrile.

The gradient employed was:

Time (min) Flow Rate (ml/min) % A % B 0 1 100 0 8 1 5 95 8.01 1 100 0

The UV detection wavelength was analyte dependent and mass spectra wererecorded on a mass spectrometer using positive ion electrospray.

Method D:

The HPLC analysis was conducted on a Phenomenex Luma C18(2) (50 mm×2mmid. 3 μm packing diameter, or validated equivalent) at 60 degreescentigrade.

Solvent A=0.05% v/v solution of TFA in Water.Solvent B=0.05% v/v solution of TFA in Acetonitrile.

The gradient employed was:

Time (min) Flow Rate (ml/min) % A % B 0 1.5 100 0 2.5 1.5 5 95 2.7 1.5 595 2.9 1.5 100 0

The UV detection wavelength was analyte dependent and mass spectra wererecorded on a mass spectrometer using positive ion electrospray.

Mass Directed Automated Preparative HPLC Methods

The methods for the mass-directed automated preparative HPLC used forthe purification of compounds are described below:

Method A—High H Column Details:

Waters_XBRIDGE Prep C18 column 5 um OBD (30×150 mm)

The solvents employed were:

A=10 mM Ammonium Bicarbonate in water adjusted to pH 10 with aq. AmmoniasolutionB=Acetonitrile+0.1% aq. Ammonia

Collection was triggered by uv, ms or a combination of the two. The UVdetection was an averaged signal from wavelength of 210 nm to 350 nm.Mass spectra were recorded on a mass spectrometer using analternate-scan positive and negative mode electrospray ionization.

Method B—Low pH Column Details:

SUNFIRE C18 column (30×150 mm id 5 uM packing diameter)

The solvents employed were:

A=0, 1% v/v solution of Formic Acid in Water.B=0.1% v/v solution of Formic Acid in Acetonitrile.

Collection was triggered by uv, ms or a combination of the two. The UVdetection was an averaged signal from wavelength of 210 nm to 350 nm.Mass spectra were recorded on a mass spectrometer using analternate-scan positive and negative mode electrospray ionization.

Preparation of Compound A Intermediates and Examples Intermediate 16-Chloro-4-iodo-1-(phenylsulfonyl)-1H-indazole

Method A

6-Chloro-4-iodo-1H-indazole (30 g, 108 mmol, available from Sinova) wasdissolved in N,N-dimethylformamide (300 ml) and cooled in an ice waterbath under nitrogen. Sodium hydride (5.17 g, 129 mmol) was addedportionwise, maintaining the temperature below 10° C. After fulladdition the reaction mixture was stirred for 20 mins thenbenzenesulfonyl chloride (16.5 ml, 129 mmol) was added dropwise over 15mins. The reaction was left to warm to RT overnight then poured onto icewater (2 L). The precipitated product was collected by filtration,washed with water (ca. 400 ml) and dried in a vacuum oven overnight togive the title compound (43.3 g).

LCMS (Method A): Rt 1.38 mins, MH⁺ 419.

Method B

To a stirred solution of 6-chloro-4-iodo-1H-indazole (633.6 g) in THF(5.7 L) was added sodium hydroxide (227.4 g) followed bytetra-n-butylammonium bisulphate (38.0 g) at 20±3° C., under a nitrogenatmosphere. The mixture was stirred at 20±3° C. for 1 h 3 min, thenbenzenesulphonyl chloride (319 ml) was added at such a rate as tomaintain the internal temperature at <25° C. Residual benzenesulphonylchloride was rinsed into the vessel with THF (630 mL), then the mixturestirred for 1 h 10 min. The mixture was cooled to <5° C. and water (12.7L) added at such a rate as to maintain internal temperature below 5±3°C., then the mixture stirred at 0-5° C. for 1 h 20 min. The solids werecollected by vacuum filtration, washed with water (2×1.9 L), sucked drythen further dried under vacuum with a nitrogen bleed at 40° C.±3° C.overnight to give the title compound (780.8 g).

LCMS (Method C): Rt 6.28 min, MH⁺ 419.

Method C

All weights, volumes and equivalents are relative to6-chloro-4-iodo-1H-indazole,

6-Chloro-4-iodo-1H-indazole (1.0 eq., 1 wt, 50 g), sodium hydroxide(2.25 eq., 0.324 wt, 16.16 g) and tetrabutylammonium hydrogensulphate(0.05 eq., 0.061 wt, 3.05 g) are stirred in THF (9.5 vols, 475 ml) at20±3° C. under a nitrogen atmosphere for 1 hr. The mixture is cooled to15±3° C. and benzenesulfonyl chloride (1.10 eq., 0.51 vols, 25.5 ml) wasadded dropwise over 20 mins maintaining the reaction temperature at <25°C. and is washed in with THF (0.5 vols, 25 ml). The resulting mixture isthen stirred under a nitrogen atmosphere at 20±3° C. for at least 1 hrbefore checking for completion by HPLC. The reaction mixture is thenadded to 0.25 M hydrochloric acid solution (18 vols, 900 ml) cooled to0±3° C. over 15 minutes maintaining the temperature of the aqueoussuspension at <20° C. This is washed in with 0.25M hydrochloric acidsolution (2 vols, 100 ml). The resulting orange suspension is thenstirred at 2±3° C. for at least 1 hr. The solid is filtered, washed withwater (2×3 vols, 2×150 ml) and sucked dry for 20 mins, then dried underhigh vacuum at 40° C. (±3° C.) to constant probe temperature to afford6-chloro-4-iodo-1-(phenylsulfonyl)-1H-indazole as an orange solid.

Intermediate 26-Chloro-1-(phenylsulfonyl)-4-(trimethylstannanyl)-1H-indazole

Chloro-4-iodo-1-(phenylsulfonyl)-1H-indazole (30 g, 71.7 mmol),tetrakis(triphenylphosphine)palladium(0) (8.1 g, 7.01 mmol), xylene (200ml), triethylamine (19.98 ml, 143 mmol) and hexamethylditin (21.8 ml,105 mmol) were heated at 150° C. for 2 h. The reaction mixture wasfiltered hot through Celite, washing with further xylene and the solventwas evaporated in vacuo. The residue was triturated with cyclohexane andthe precipitate collected by filtration and dried in a vacuum oven togive the title compound (14.4 g).

LCMS (Method A): Rt 1.51 mins, MH⁺ 457.

Intermediate 3a Ethyl2-[6-chloro-1-(phenylsulfonyl)-1-indazol-4-yl]-1,3-oxazole-5-carboxylate

In 4 batches, tetrakis(triphenylphosphine)palladium(0) (3.37 g, 2.92mmol), ethyl 2-chloro-1,3-oxazole-5-carboxylate (6.65 g, 37.9 mmol,available from Apollo Scientific) and copper(I) iodide (1.11 g, 5.83mmol) were added to a solution of6-chloro-1-(phenylsulfonyl)-4-(trimethylstannanyl)-1H-indazole (13.28 g,29.2 mmol) in N,N-dimethylformamide (52 ml). In 3 of the batches,tetrakis(triphenylphosphine)palladium(0) (1.03 g, 0.89 mmol), ethyl2-chloro-1,3-oxazole-5-carboxylate (2.03 g, 11.59 mmol) and copper(I)iodide (0.34 g, 1.78 mmol) were added to a solution of6-chloro-1-(phenylsulfonyl)-4-(trimethylstannanyl)-1H-indazole (4.06 g,8.91 mmol) in N,N-dimethylformamide (16 ml). In the fourth batch,tetrakis(triphenylphosphine)palladium(0) (0.28 g, 0.24 mmol), ethyl2-chloro-1,3-oxazole-5-carboxylate (0.55 g, 3.14 mmol) and copper(I)iodide (0.09 g, 0.48 mmol) were added to a solution of6-chloro-1-(phenylsulfonyl)-4-(trimethylstannanyl)-1H-indazole (1.10 g,2.42 mmol) in N,N-dimethylformamide (4 ml). Each batch was heated andstirred at 100° C. under microwave irradiation for 30 min. The mixtureswere allowed to cool to RT and the combined precipitated productsuspended in diethyl ether and collected by filtration, washing withfurther diethyl ether then drying in a vacuum oven for 72 h.Approximately 5.2 g of the resultant solid was dissolved indichloromethane and passed through Celite, eluting with furtherdichloromethane. The solvent was evaporated in vacuo to give the titlecompound as a pale orange solid (4.95 g),

LCMS (Method A); Rt 1.38 mins, MH⁺ 432.

Intermediate 3b Methyl2-[6-chloro-1-(phenylsulfonyl)-1H-indazol-4-yl]-1,3-oxazole-5-carboxylate

To a stirred solution of 6-chloro-4-iodo-1-(phenylsulphonyl)-1H-indazole(549.8 g) in toluene (1.43 L) was added triethylamine (380 ml) at 20±3°C. under an atmosphere of nitrogen. Hexamethylditin (385 ml) in toluene(825 ml) was added, followed by toluene (275 ml) thentetrakis(triphenylphosphine) palladium (0) (154.7 g). The reactionmixture was heated to 120° C. and stirred at this temperature for 3 h.The mixture was allowed to cool to 20±3° C., filtered, then washed withtoluene (4.95 L). The filtrate was transferred to a clean vessel througha 5 μm Dominick hunter in-line filter, rinsing with further toluene (550ml). The batch was then washed with 50% aqueous KF solution (5.5 L), theaqueous slurry filtered and the filtrate recombined with the organicphase. The aqueous was separated and the organics washed successivelywith 50% aqueous KF (5.5 L), followed by water (5.5 L). The organiclayer was diluted with DMPU (2.75 L) then concentrated by vacuumdistillation to ca. 5.4 vols. To the resultant solution was added copper(I) iodide (25.5 g) followed by methyl2-chloro-1,3-oxazole-5-carboxylate (279 g, available from ApolloScientific) at 20±30°. The solution was degassed via vacuum and nitrogenpurges (×3). Tetrakis(triphenylphosphine) palladium (0) (78 g) wasadded, the mixture degassed (×3) and then heated to 85-90° C. for 10 h.The mixture was diluted with DMSO (13.75 L) and cooled to 20±3° C., thenwater (2.75 L) added in ca. 1 vol portions over ca. 15 mins untilcrystallisation was initiated. The resultant suspension was aged at 20°C.±3° C. for 1.5 h. The solids were collected by vacuum filtration,washed with water (2×2.75 L), sucked dry and then further dried in vacuowith a nitrogen bleed at 45° C.±5° C. overnight to give the titlecompound (341.1 g).

LCMS (Method C): Rt 6.08 mins, MH⁺ 418

Intermediate 4{2-[6-Chloro-1-(phenylsulfonyl)-1H-indazol-4-yl]-1,3-oxazol-5-yl}methanol

Method A

A solution of ethyl2-[6-chloro-1-(phenylsulfonyl)-1H-indazol-4-yl]-1,3-oxazole-5-carboxylate(5.11 g, 11.8 mmol) in dichloromethane (80 ml) was cooled to −25° C. inan oven dried round bottomed flask. Diisobutylaluminium hydride (25 ml,37.5 mmol, 1.5M solution in toluene) was added dropwise and the reactionstirred at −20° C. for 3 h. A 10% aqueous solution of potassium sodiumtartrate (80 ml) was added and the reaction mixture stirred for 5 min.The precipitated solid was filtered off and partitioned between ethylacetate (500 ml) and water (500 ml). The layers were separated and theaqueous washed with further ethyl acetate (3×150 ml). The combinedorganics were dried and evaporated in vacuo to give the title compoundas a yellow solid (1.1 g).

LCMS (Method A): Rt 1.09 mins, MH⁺ 390.

The remaining filtrate was largely concentrated in vacuo and the residuepartitioned between ethyl acetate (500 ml) and water (500 ml). Thelayers were separated and the aqueous extracted with further ethylacetate (3×150 ml). The combined organics were washed with water (2×150ml), dried over anhydrous sodium sulfate and evaporated to give thetitle compound as a yellow solid (1.9 g).

LCMS (Method A): Rt 1.09 mins, MH⁺ 390.

Method B

To a solution of ethyl2-[6-chloro-1-(phenylsulfonyl)-1H-indazol-4-yl]-1,3-oxazole-5-carboxylate(1.15 g) in THF (17.25 ml), stirred under nitrogen in an ice bath wasadded a solution of diisobutylaluminum hydride (5.08 ml, 5.64 mmol) intoluene. The reaction mixture was stirred at 0° C. for 2 h. Sodiumsulphate decahydrate (2.5 g) was added, the mixture stirred at RT for 1h, then filtered, washed with THF (2×5 vols) and concentrated underreduced pressure to give the title compound (0.98 g).

LCMS (Method D): Rt 2.20 mins, MH⁺ 390.

Method C

To a solution of ethyl2-[6-chloro-1-(phenylsulfonyl)-1H-indazol-4-yl]-1,3-oxazole-5-carboxylate(604.5 g) in THF (8.7 L), stirred under nitrogen at 0±3° C. was added asolution of approximately 1.3M diisobutylaluminum hydride (1.8 kg) intoluene. The reaction mixture was stirred at 0±3° C. for 30 mins andthen diluted with THF (3 L). Sodium sulphate decahydrate (1.3 kg) wasadded, maintaining the temperature below 5° C. The mixture was stirredat 0±3° C. for 10 mins and was then warmed to 20±3° C. and held at thistemperature for 1 h. The suspension was filtered, washed with THF (4×3L) and concentrated under reduced pressure to give the title compound(529.6 g).

LCMS (Method C): Rt 5.18 min, MH⁺ 390.

Method D

All weights, volumes and equivalents are relative to6-chloro-4-iodo-1-(phenylsulfonyl)-1H-indazole.

Zinc chloride (3.6 eq, 1.17 wt, 52.7 g) in tetrahydrofuran (5 vols, 225ml) is cooled to 0 to 5° C. A solution of the ethyloxazole-5-carboxylate (1.1 eq, 0.37 wt, 18.1 g, corrected for 92 wt %assay) in tetrahydrofuran (5 vols, 225 ml) is added to the vessel. Thesuspension is cooled to −10° C. (+/−5° C.) under a nitrogen atmosphereand a 1M solution of bis-(trimethylsilyl)-lithiumamide intetrahydrofuran (1.80 eq, 4.30 vols, 193 ml) is added over 15 minutesmaintaining the temperature at −10° C. (+/−5° C.). The resultingsolution is stirred under a nitrogen atmosphere at −10° C. (+/−5° C.)for 1 hour. To the solution is added6-chloro-4-iodo-1-(phenylsulfonyl)-1H-indazole (1.0 eq, 1.0 wt, 45.0 g)and tetrakis triphenylphosphine palladium (0.03 eq, 0.083 wt, 3.73 g)(the mixture is degassed with vacuum/nitrogen 3 times) and then heatedto 60° C. (+/−3° C.) for at least 6 hours. The reaction is then checkedby HPLC for completion. The reaction solution is cooled to 0° C. (+/−3°C.) and a solution of 25% w/w diisobutylaluminum hydride in toluene (4.0eq, 6.4 vols, 288 ml) is added maintaining the temperature at <5° C. Theresulting reaction solution is then stirred at 0° C. (+/−3° C.) for atleast 1 hour. The reaction is then checked by HPLC (generic) forcompletion. The reaction mixture is added portion wise to a solution ofcitric acid (4.0 eq, 2.0 wt, 90 g) in water (10 vols, 450 ml) at 0° C.(+/−5° C.) over ˜1 h. The resulting solution is stirred at 20° C. for 15minutes, extracted with ethyl acetate (10 vols, 450 ml), the organiclayer is washed with water (2×3 vols, 2×135 ml) and filtered through aporosity 4 sinter. The organic layer is then evaporated under reducedpressure (45° C., 100 mbar) to 2 to 3 volumes, dimethyl sulphoxide (10vols, 450 ml) is added and the solution evaporated under reducedpressure (45° C., 50 mbar) to remove all traces of other solvents. Tothe solution at 45° C. is added water (5 vols, 225 ml) dropwise over 30minutes, the resulting reaction mixture is cooled to 20° C. over 3 hrand stirred at 20° C. for at least 15 hrs. The product is filtered,washed with a solution of dimethylsulphoxide:water (1:2) (2 vols, 90ml), then washed with water (3 vols, 135 ml), then dried under highvacuum at 60° C. (±3° C.) to constant probe temperature to afford(2-(6-chloro-1-(phenylsulfonyl)-1H-indazol-4-yl)oxazol-5-yl)methanol asa beige solid.

Intermediate 54-[5-(Bromomethyl)-1,3-oxazol-2-yl]-6-chloro-1-(phenylsulfonyl)-1H-indazole

Method A

{2-[6-Chloro-1-(phenylsulfonyl)-1H-indazol-4-yl]-1,3-oxazol-5-yl}methanol(1.626 g, 4.17 mmol) was dissolved in anhydrous dichloromethane (20 ml)and carbon tetrabromide (2.77 g, 8.34 mmol) added. The reaction mixturewas cooled to 0° C. and a solution of triphenylphosphine (2.188 g, 8.34mmol) in dichloromethane (20 ml) added dropwise. After allowing to warmto RT and stirring for a further 3 h, the solvent was partially removedin vacuo and the solution purified directly by silica gelchromatography, eluting with 0-100% ethyl acetate in dichloromethane.The appropriate fractions were combined to give the title compound as acream solid (1.16 g),

LCMS (Method B): Rt 3.70 mins, MH⁺ 454.

Method B

Triphenylphosphine dibromide (20.60 g, 48.8 mmol) was added to asuspension of{2-[6-chloro-1-(phenylsulfonyl)-1H-indazol-4-yl]-1,3-oxazol-5-yl}methanol(9.06 g, 23.2 mmol) in dichloromethane (181 ml) at 0° C. The reactionmixture was stirred at 0° C. until completion. Water (91 ml) andsaturated sodium bicarbonate solution (91 ml) were added and the mixturestirred, then separated. The aqueous layer was extracted with furtherdichloromethane (45 ml) and the organics combined and washed with water(91 ml). The layers were separated and the organic concentrated todryness then redissolved in methanol (136 ml). After stirring for 30mins the resultant white suspension was filtered and the solid driedunder vacuum to give the title compound as an off-white solid (9.58 g).

LCMS (Method D): Rt 2.57 min, MH⁺ 452/454.

Method C

Triphenylphosphine dibromide (1.2 kg) was added to a suspension of{2-[6-chloro-1-(phenylsulfonyl)-1H-indazol-4-yl}-1,3-oxazol-5-ylmethanol(544.7 g) in dichloromethane (3.8 L) stirred under nitrogen at 10±3° C.The reaction mixture was stirred at 10±3° C. for 20 min. Water (2.7 L)and saturated sodium bicarbonate solution (5.4 L) were added and themixture stirred, then separated. The aqueous layer was extracted withfurther dichloromethane (2.7 L) and the organics combined and washedwith water (2.7 L). The layers were separated and the organicconcentrated to dryness then redissolved in methanol (6.5 L). Afterstirring for 5 hours the resultant white suspension was filtered, washedwith methanol (2×1.1 L) and the solid dried under vacuum at 40±5° C. togive the title compound as an off-white solid (514.0 g).

LCMS (Method C): Rt 6.40 min, MH⁺ 453/455.

Method D

All weights, volumes and equivalents are relative to(2-(6-chloro-1-(phenylsulfonyl)-1H-indazol-4-yl)oxazol-5-yl)methanol.

(2-(6-Chloro-1-(phenylsulfonyl)-1H-indazol-4-yl)oxazol-5-yl)methanol(1.0 eq., 1 wt, 34.0 g) and triphenylphosphine dibromide (1.3 eq., 1.32wt, 45.0 g) are stirred in dichloromethane (15 vols, 510 ml) at 20 (±3°C.) under a nitrogen atmosphere for 1 hr. The reaction is then checkedby HPLC for completion. Once complete methanol (0.8 vols, 27.2 ml) isadded to the reaction, with vigorous stirring 8% w/w sodium hydrogencarbonate solution (10 vols, 340 ml) is added drop wise over 15 minutes(check aqueous pH>7). The mixture is heated to 3° C. (±3° C.) andstirred together for 10 minutes, then separated, the aqueous is backextracted with dichloromethane (5 vols, 170 ml) and the combineddichloromethane layers are washed with water (5 vols, 170 ml). Thedichloromethane solution is then evaporated under reduced pressure to avolume of approximately 4 vols. To the solution is added methanol (15vols, 510 ml) and the solution evaporated under reduced pressure at 260mbar, 20° C. to remove the remaining dichloromethane down to ˜15 vols.The suspension is then stirred at 20° C. for at least 6 hrs. The solidis filtered, washed with methanol (2×1 vols, 2×34 ml), sucked dry for 20minutes, then dried under high vacuum at 30° C. (±3° C.) to constantprobe temperature to afford5-(bromomethyl)-2-(6-chloro-1-(phenylsulfonyl)-1H-indazol-4-yl)oxazoleas a beige solid.

Intermediate 66-Chloro-4-(5-{[(2R,6S)-2,6-dimethyl-4-morpholinyl]methyl}-1,3-oxazol-2-yl)-1-(phenylsulfonyl)-1H-indazole

Method A

4-[5-(Bromomethyl)-1,3-oxazol-2-yl]-6-chloro-1-(phenylsulfonyl)-1H-indazole(0.580 g, 1.28 mmol) was dissolved in dichloromethane (5 ml) and(2R,6S)-2,6-dimethylmorpholine (0.317 ml, 2.56 mmol) added. The reactionmixture was stirred at RT for 3 h then the solvent removed under astream of nitrogen. The resultant yellow solid was dissolved indichloromethane (5 ml) and washed with water (2×2.5 ml). The layers wereseparated (hydrophobic frit) and the organic evaporated in vacuo to givethe title compound as a pale yellow solid (0.60 g).

LCMS (Method A): Rt 0.86 mins, MH⁺ 487.

¹H NMR (400 MHz, Chloroform-d) δ (ppm) 8.93 (d, J=1.0 Hz, 1H), 8.33 (dd,J=1.0, 1.5 Hz, 1H), 8.04-8.00 (m, 2H), 7.98 (d, J=1.5 Hz, 1H), 7.62 (tt,J=1.5, 7.5 Hz, 1H), 7.51 (t, J=7.5 Hz, 2H), 7.15 (s, 1H), 3.67 (s, 2H),3.75-3.66 (m, 2H), 2.79-2.72 (m, 2H), 1.86 (dd, J=10.5, 11.0 Hz, 2H),1.16 (d, J=6.5 Hz, 8H).

Method B

(2R,6S)-2,6-dimethylmorpholine (160 ml) and then triethylamine (180 ml)were added to a suspension of4-[5-(Bromomethyl)-1,3-oxazol-2-yl]-6-chloro-1-(phenylsulfonyl)-1H-indazole(478.1 g) in acetone (3.8 L) stirred under nitrogen at less than 25° C.The reaction mixture was stirred at 20-25° C. for 2.5 hours and thenwater (3.8 L) was added. The resultant suspension was stirred at than25° C. for 35 min and was then filtered, washed with a mixture of 2:1v/v water:acetone (2×1.0 L) and the solid dried under vacuum at 45±5° C.to give the title compound as an off-white solid (500.5 g).

LCMS (Method B): Rt 3.43 min, MH⁺ 487.

Method C

All weights, volumes and equivalents are relative to5-(bromomethyl)-2-(6-chloro-1-(phenylsulfonyl)-1H-indazol-4-yl)oxazole(corrected for assay).

To a suspension of5-(bromomethyl)-2-(6-chloro-1-(phenylsulfonyl)-1H-1-indazol-4-yl)oxazole(1 wt, 540 g) in acetone (8.7 vol, 4.7 L) is added2,6-dimethylmorpholine (0.33 vol, 1.2 eq, 178 ml), followed bytriethylamine (0.37 vol, 1.2 eq, 200 ml) at <25° C. under a nitrogenatmosphere. The resulting mixture is stirred at 20-25° C. for at least0.5 hr, then monitored for completion by HPLC. Water (8.7 vol, 4.7 L) isthen added to the mixture over ca 5 minutes. The resulting suspension isaged at <25° C. for at least 0.5 hr, then the solids are collected byvacuum filtration, washed with water/acetone (2:1 v/v, 2×2.2 vol, 2×1.2L) and dried in vacuo with a nitrogen bleed at 45±5° C.

Recrystalisation—All weights, volumes and equivalents are relative to((2-(6-chloro-1-(phenylsulfonyl)-1H-indazol-4-yl)oxazol-5-yl)methyl)-cis-2,6-dimethylmorpholine.A stirred suspension of((2-(6-chloro-1-(phenylsulfonyl)-1H-indazol-4-yl)oxazol-5-yl)methyl)-cis-2,6-dimethylmorpholine(1 wt, 30 g) in DMSO (9 vol, 270 ml) is heated to 75-80° C. under anitrogen atmosphere. The resulting clear solution is transferred to acrystallising vessel via a 5 μm Domnick hunter in line filter, then theline is washed with further DMSO (1.0 vol, 30 ml). The hot solution isallowed to cool to 20-25° C. over at least 2 hr, then the resultingsuspension is aged at this temperature for at least 1 hr. The resultingsolids are filtered, washed with DMSO (1.5 vol, 45 ml), followed bywater/acetone (2:1 v/v, 2×2 vol, 2×60 ml) before being sucked dry for0.5 hr. The batch is dried in vacuo at 45° C. to constant probetemperature to afford((2-(6-chloro-1-(phenylsulfonyl)-1H-indazol-4-yl)oxazol-5-yl)methyl)-cis-2,6-dimethylmorpholineas an off-white solid.

Intermediate 72-(Methyloxy)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-pyridinamine

To 5-bromo-2-(methyloxy)-3-pyridinamine (18.93 g, 93 mmol, availablefrom Asymchem International) in a 1 L round-bottom flask was addednitrogen-purged 1,4-dioxane (500 ml) followed by4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi-1,3,2-dioxaborolane (47.4 g, 186mmol), potassium acetate (27.5 g, 280 mmol) anddichloro{1,1′-bis(diphenylphosphino)ferrocene]palladium(II)dichloromethane adduct (7.61 g, 9.32 mmol). The mixture was thenstirred at 80° C. under nitrogen for 2 h. The reaction mixture wasallowed to cool then partitioned between ethyl acetate and water andfiltered through a Celite pad. The aqueous layer was extracted furtherwith ethyl acetate (2×) and the combined organics washed with water,brine and dried over magnesium sulphate overnight. The mixture wasfiltered and the filtrate concentrated in vacuo to give a dark brownsolid. The residue was purified by silica gel chromatography, eluting in0-50% ethyl acetate/dichloromethane. The appropriate fractions werecombined and evaporated to dryness and the residue triturated withcyclohexane. The resultant solid was filtered off and dried in vacuo togive the title compound as a light pink solid (11.1 g).

LCMS (Method A) Rt 0.91 mins, MH⁺ 251.

Intermediate 8N-[2-(Methyloxy)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-pyridinyl]methanesulfonamide

To a solution of2-(methyloxy)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-pyridinamine(0.5 g, 1.999 mmol) in pyridine (5 ml) was added methanesulphonylchloride (0.309 ml, 4.00 mmol) and the mixture stirred at 20° C. for 18hr then the solvent was removed in vacuo. The residue was partitionedbetween saturated sodium bicarbonate solution (10 ml) anddichloromethane (20 ml), separated by hydrophobic frit and purified bysilica gel chromatography, eluting with a gradient of dichloromethaneand methanol to give the title compound as a brown solid (0.46 g).

LCMS (Method A): Rt 0.98 mins, MH⁺ 329.

Intermediate 9N-[5-[4-(5-{[(2R,6S)-2,6-Dimethyl-4-morpholinyl]methyl}-1,3-oxazol-2-yl)-1-(phenylsulfonyl)-1H-indazol-6-yl]-2-(methyloxy)-3-pyridinyl]methanesulfonamide

Method A

A suspension of palladium (II) acetate (0.05 g) andtricyclohexylphosphine (0.16 g) in isopropanol (27 ml) was added to asuspension of6-Chloro-4-(5-{[(2R,6S)-2,6-dimethyl-4-morpholinyl]methyl}-1,3-oxazol-2-yl)-1-(phenylsulfonyl)-1H-indazole(5.40 g), Potassiumtrifluoro{6-(methyloxy)-5-[(methylsulfonyl)amino]-3-pyridinyl}borate(6.19 g) and sodium bicarbonate (2.87 g) in isopropanol (27 ml) andwater (38 ml) stirring under nitrogen at 60-65° C. The reaction mixturewas stirred at 60-65° C. for 2.5 hours and was then cooled to roomtemperature. The resultant suspension was filtered, washed with 1:1 v/vwater isopropanol (11 ml then 22 ml) and the solid dried under vacuum at40° C. to give the title compound as a grey solid (7.73 g).

LCMS (Method B): Rt 2.59 min, MH⁺ 653.

Method B

All weights, volumes and equivalents are relative to((2-(6-chloro-1-(phenylsulfonyl)-1H-indazol-4-yl)oxazol-5-yl)methyl)-cis-2,6-dimethylmorpholine.

((2-(6-Chloro-1-(phenylsulfonyl)-1H-indazol-4-yl)oxazol-5-yl)methyl)-cis-2,6-dimethylmorpholine(1.00 wt, 460 g),N-(2-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-yl)methanesulfonamide(0.741 wt, 1.1 eq, 341 g) and potassium phosphate (0.523 wt, 1.2 eq, 241g) are combined in IPA (5 vol, 2.3 L) and water (5 vol, 2.3 L) in aclean CLR under nitrogen. Potassium hydrogen difluoride (0.353 wt, 2.2eq. 163 g) is added and the mixture is heated to 75-80° C. and degassedat this temperature for at least 1 hr. In a separate vessel IPA (5 vol,2.3 L) is degassed by being heated to reflux, then stirred for a further20 min at this temperature under a flow of N₂ before being cooled to20-25° C. under a nitrogen atmosphere. To the degassed IPA (5 vol, 2.3L) is charged palladium (II) acetate (0.00922 wt, 0.02 eq, 4.25 g),followed by tricyclohexylphosphine (0.0230 wt, 0.04 eq, 10.6 g) and themixture stirred at 20-25° C. for at least 0.5 hr. The resultant yellowsolution is added to the reaction mixture and stirred at 75-80° C. forat least 2 hr, then monitored for completion by HPLC. The mixture iscooled to 30° C. over 1 hr and water (5 vol, 2.3 L) is added. The slurryis allowed to cool to 20° C., then aged at this temperature for at least0.5 hr, filtered, washed with IPA:water (1:1 v/v, 2×2 vol, 2×920 ml) andsucked dry. The solid is dried in vacuo at 60° C. to constant probetemperature to affordN-(5-(4-(5-((cis-2,6-dimethylmorpholino)methyl)oxazol-2-yl)-1-(phenylsulfonyl)-1H-indazol-6-yl)-2-methoxypyridin-3-yl)methanesulfonamideas an off-white solid.

Intermediate 10 5-Bromo-2-(methyloxy)-3-nitropyridine

Method A

A solution of 25% wt sodium methoxide in methanol (2.1 L) was added to asuspension of 5-bromo-2-chloro-3-nitropyridine (1.70 kg) in methanol(6.6 L), stirred under nitrogen at 0-5° C. The reaction mixture wasstirred at 5-10° C. for 2.75 hours and then water (8.5 L) was added. Thereaction mixture was cooled to 20-25° C. The mixture was thenconcentrated under vacuum and the resultant suspension was filtered,washed with water (8.5 L then 2×4.25 L) and the solid dried under vacuumto give the title compound as an off-white solid (1.37 kg).

¹H NMR (400 MHz, Chloroform-d) δ (ppm) 8.46 (s, 1H), 8.40 (s, 1H).

Method B

All weights, volumes and equivalents are relative to5-bromo-2-chloro-3-nitropyridine.

To a suspension of 5-bromo-2-chloro-3-nitropyridine (75.0 g, 1 wt, 1 eq)in methanol (300 mL, 4 vols), is added a solution of sodium methoxide inmethanol (25 wt %, 88.6 g, 1.3 eq) over approximately 1 hour so as tomaintain the internal temperature at 20±5° C. The mixture is stirred at20° C. for at least 0.5 hr, then monitored for completion by HPLC. Water(375 mL, 5 vols) is then added to the mixture at such a rate as tomaintain the internal temperature below 30° C., then aged at thistemperature for at least 0.5 hr. The batch is then concentrated to 6vols in vacuo. The resulting slurry is allowed to cool to 20-25° C.,then collected by vacuum filtration, washed with water and dried invacuo with a nitrogen bleed at 20-25° C. to constant weight to afford5-bromo-2-methoxy-3-nitropyridine as a white solid.

Intermediate 11 6-Bromo-2-(methyloxy)-3-pyridinamine

Iron powder (1.17 kg) was added to a suspension of5-bromo-2-(methyloxy)-3-nitropyridine (1.36 kg) in IMS (6.1 L), stirredunder nitrogen at 20-25° C. Water (0.8 L) was then added and the mixturecooled to less than 10° C. Aqueous hydrochloric acid (0.8 L concentratedhydrochloric acid and 0.8 L water) was then added to the reactionmixture, maintaining the temperature below 10-150°. The suspension waswarmed to 20-25° C. and then stirred at this temperature for 23 hours.The suspension was filtered, the filter cake washed with IMS (2×2.7 L)and the combined filtrates concentrated under vacuum. Water (4.1 L) wasadded slowly to the concentrated solution and the resulting suspensionwas held at 20-25° C. for 1.75 hours. The resultant suspension wasfiltered, washed with water (2×6.8 L) and the solid dried under vacuumto give the title compound as an off-white solid (1.13 kg).

LCMS (Method B): Rt 2.16 min, MH⁺ 204.

Intermediate 12 N-[5-Bromo-2-(methyloxy)-3-pyridinyl]methanesulfonamide

Method A

Pyridine (540 ml) was added to a suspension of5-bromo-2-(methyloxy)-3-pyridinamine (902.0 g) in acetonitrile (2.1 L),stirred under nitrogen at less than 25° C. The mixture was cooled toless than 10° C. and methanesulfonyl chloride (605.3 g) was addedmaintaining the temperature below 25° C. The reaction mixture wasstirred at 15-25° C. for 3 hours. Water (3.6 L) was added slowly to themixture over 1 hour, maintaining the temperature below 25° C. Theresultant suspension was filtered, washed with 3:1 v/vwater:acetonitrile (2×1.35 L and the solid dried under vacuum at 45±5°C. to give the title compound as an off-white solid (1.13 kg).

LCMS (Method B): Rt 1.42 min, MH⁺ 282.

Method B

All weights, volumes and equivalents are relative to5-bromo-2-methoxypyridin-3-amine hydrochloride.

5-Bromo-2-methoxypyridin-3-amine hydrochloride (100 g, 1 wt, 1 eq) ischarged to a CLR containing a mixture of acetonitrile (220 mL, 2.2 vols)and pyridine (101 mL, 1.01 vols, 99 g, 0.99 wt) at room temperature.Methanesulfonyl chloride (56.4 g, 0.564 wt, 1.18 eq) is then added tothe mixture over 20 minutes whilst maintaining the temperature at 20° C.Having stirred at 20° C. for a further 1.5 hours, the mixture is sampledand analysed by HPLC. The completed reaction is quenched by the additionof water over 1 hour, maintaining the mixture at 20° C. and withincreased stirrer speed. The resulting slurry is stirred for 17 hoursand then filtered in vacuo. The cake is washed with 3:1water:acetonitrile (2×50 mL, 2×0.5 vols) and then dried under vacuum at40-45° C. to afford N-(5-bromo-2-methoxypyridin-3-yl)methanesulfonamide.

Intermediate 13 Potassiumtrifluoro{6-(methyloxy)-5-[(methylsulfonyl)amino]-3-pyridinyl}borate

N-[5-bromo-2-(methyloxy)-3-pyridinyl]methanesulfonamide (499.4 g),bis(pinacolato)diboron (498.2 g) and potassium acetate (361.8 g) werecharged to the reaction vessel. The reaction vessel was purged withnitrogen for 10 min before 1,4-dioxane (8.0 L) was added. The resultantsolution was heated to 95±5° C. and stirred under nitrogen at thistemperature. A degassed solution of tris(dibenzylideneacetone)dipalladium (0) (16.6 g) and tricyclohexylphosphine (25.0 g) in1,4-dioxane (2.5 L) was added to the reaction vessel over 30 min. Thereaction mixture was then stirred at 95±5° C. for 14 hours. The mixturewas cooled to 20±3° C. and held at this temperature for 1 hour. Thereaction mixture was filtered and concentrated under vacuum. Water (1.0L) and potassium hydrogenfluoride (555.0 g) were added and the resultantmixture was stirred for 1 hour. Water (2.0 L) was added to thesuspension, the aqueous layer was removed and the remaining organiclayer was filtered. 1,4-dioxane (12.0 L) was added to the solution whichwas then dried by azeotropic vacuum distillation. Upon completedistillation the mixture was cooled to 20±3° C. and held at thistemperature for 30 min. The resultant suspension was filtered, washedwith 1,4-dioxane (2×1 L), then t-butyl methyl ether (2×1.0 L) and thesolid dried under vacuum to give the title compound as an off-whitesolid (708.3 g).

LCMS (Method C): Rt 2.26 min, MH⁺ 247.

Intermediate 14 Ethyl oxazole-5-carboxylate

All weights, volumes and equivalents are relative totoluenesulfonylmethyl isocyanide.

Toluenesulfonylmethyl isocyanide (TosMIc) (12.31 g, 1 wt, 1 eq) isdissolved in DCM (61.6 ml, 5 vols) at 0° C. under N₂. In a separatevessel, ethyl glyoxylate (50 wt % solution in toluene, 20.6 g, 20.0 ml,1.67 wt) is diluted with DCM (61.6 ml, 5 vols) under N₂ and DBU (12.48g, 12.35 ml, 1.3 eq, 1.01 wt) is added resulting in a purple solution.The second solution is added to the TosMIc solution over 1 hr,maintaining temperature at 0° C., then checked by HPLC for completionafter a further 20 mins. The reaction is quenched by slow addition of 2MHCl (10 vols, 123 ml) and the DCM layer separated. The aqueous layer isre-extracted with DCM (5 vols, 61.6 ml), and the combined organics driedover Na₂SO₄, then evaporated on Buchi, 25° C., 100 mbar to remove DCMand toluene. Distilled at 12 mbar, jacket temperature 105° C., vapourtemperature 60-80° C. to afford ethyl oxazole-5-carboxylate as acolourless oil.

Intermediate 15 5-Bromo-2-methoxypyridin-3-amine

All weights, volumes and equivalents are relative to5-bromo-2-methoxy-3-nitropyridine.

To a nitrogen-purged flask is charged 5-bromo-2-methoxy-3-nitropyridine(1 wt, 5.0 g) and iron powder (325 mesh, 0.86 wt, 4.31 g). IMS (12 vols,60 ml) is added water (0.6 vols, 3 ml) and the mixture is heated to35-40° C. with vigorous stirring. A mixture of concentrated HCl (37 wt%, 0.146 vols, 0.73 ml) and water (0.56 vols, 2.8 ml) is prepared. Theacid solution is added to the reaction over at least 2.5 hrs at 35-40°C. The reaction is stirred for at least a further 1.5 hrs and sampledfor completion test by HPLC. The reaction is cooled, filtered throughCelite and the vessel and bed washed with IMS (2×2 vols, 2×10 ml). Thecombined filtrates are distilled under vacuum to 5 vols and toluene (10vols, 50 ml) is added, the mixture is distilled, this is repeated untilthe level of IMS is <5% by NMR. The solution is cooled and 5M HCl in IPA(0.9 vols, 1.05 eq, 4.5 ml), is added over at least 30 mins. Theresultant slurry is stirred for at least 60 mins, filtered and the cakewashed with toluene (2×2 vols, 2×10 ml). The cake is dried under vacuumat 40° C. overnight to afford 5-bromo-2-methoxypyridin-3-aminehydrochloride as a white solid.

Intermediate 16N-(2-Methoxy-5(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-yl)methanesulfonamide

All weights, volumes and equivalents are relative toN-(5-bromo-2-methoxypyridin-3-yl)methanesulfonamide.

Tricyclohexylphosphine (0.1191 g, 0.425 mmol, 0.008 eq, 0.008 wt) andPd₂(dba)₃ (0.1438 g, 0.157 mmol, 0.003 eq, 0.01 wt) are mixed togetherand then toluene (15.00 mL, 1 vol, 0.86 wt, sparged with nitrogen for 1hr) is added. The mixture is stirred and heated to 40-45° C. for 45 minsbefore being allowed to cool back to room temp and sit under nitrogen togive an orange-gold solution with suspended black particulates. In aseparate vessel, N-(5-bromo-2-methoxypyridin-3-yl)methanesulfonamide(15.0323 g, 53.5 mmol, 1 wt, 1 eq), bis(pinacolato)diboron (16.2962 g,64.2 mmol, 1.2 eq, 1.08 wt) and potassium acetate (10.4879 g, 107 mmol,2 eq, 0.70 wt) are mixed together with toluene (150 mL, 10 vols, 8.6wt). The resultant slurry is stirred and heated to 90° C. under a flowof nitrogen. Having reached the desired temperature, the catalystmixture is added over 10 minutes followed by a wash of toluene (7.50 mL,0.5 vol, 0.43 wt). The mixture is stirred at 90° C. for at least onehour and then sampled for HPLC analysis. Once complete, the reactionmixture is cooled to 50° C. and filtered to remove inorganic material.The filtered solid is washed with toluene (2×15 mL, 2×1 vol, 2×0.86 wt)and the liquors and washes combined and distilled down to 5 vols. Theproduct solution is allowed to cool to room temperature by which stageit has become a slurry. Heptane (75 mL, 5 vols, 3.4 wt) is slowly addedto the slurry. The slurry is aged and the supernatant analysed by HPLCto ensure sufficient crystallisation has occurred. The slurry isfiltered and the solid product is washed with 1:1 toluene:heptane (2×15mL, 2×1 vol) and dried under vacuum at 40-50° C. to affordN-(2-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-yl)methanesulfonamideas an off-white solid.

Recrystallisation—All weights, volumes and equivalents are relative toN-(2-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-yl)methanesulfonamide.A stirred suspension ofN-(2-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-yl)methanesulfonamide(1 wt, 1.01 kg) in propan-2-ol (4 vol, 4.05 L) is heated to 70-75° C.under a nitrogen atmosphere, then aged at this temperature for at least2 hr. The batch is allowed to cool to 20-25° C. over at least 1 hr, thenthe suspension is aged at this temperature for a further 1 hr. Theliquors are sampled by HPLC to ensure complete crystallisation, then theresulting solids are filtered, washed with propan-2-ol (2×1 vol, 2×1.01L) before being sucked dry for 0.5 hr, then the batch is dried in vacuoat 50° C. to constant probe temperature to affordN-(2-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-yl)methanesulfonamideas a white solid.

Example 1N-[5-[4-(5-{[(2R,6S)-2,6-Dimethyl-4-morpholinyl]methyl}-1,3-oxazol-2-yl)-1H-indazol-6-yl]-2-(methyloxy)-3-pyridinyl]methanesulfonamide

Method A

To a solution of6-chloro-4-(5-{[(2R,6S)-2,6-dimethyl-4-morpholinyl]methyl}-1,3-oxazol-2-yl)-1-(phenylsulfonyl)-1H-indazole(0.20 g, 0.411 mmol) andN-[2-(methoxy)-5-(4,4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-pyridyl]methanesulfonamide(0.175 g, 0.534 mmol) in 1,4-dioxane (2 ml) was addedchloro[2′-(dimethylamino)-2-biphenylyl]palladium-1(1R,4S)-bicyclo[2.2.1]hept-2-yl[(1S,4R)-bicyclo[2.2.1]hept-2-yl]phosphane(11.5 mg, 0.021 mmol), potassium phosphate tribasic (0.262 g, 1.23 mmol)and water (0.2 ml). The reaction mixture was heated and stirred at 120°C. under microwave irradiation for 1 h. Additionalchloro[2′-(dimethylamino)-2-biphenylyl]palladium-(1R,4S)-bicyclo[2.2.21]hept-2-yl[(1S,4R)-bicyclo[2.2.1]hept-2-yl]phosphane(11.5 mg, 0.021 mmol) and potassium phosphate tribasic (80 mg) wereadded and the reaction heated to 1200° C. under microwave irradiationfor 1 h. Additional potassium phosphate tribasic (80 mg) was added andthe reaction heated under the same conditions for a further 1 h. Thereaction mixture was filtered through a silica SPE and eluted withmethanol. The solvent was removed in vacuo and the residue partitionedbetween dichloromethane (5 ml) and water (5 ml). The layers wereseparated and the aqueous extracted with further dichloromethane (2×2ml). The combined organics were concentrated under a stream of nitrogenand the residue dissolved in MeOH:DMSO (3 ml, 1:1, v/v) and purified byMDAP (method A) in 3 injections. The appropriate fractions were combinedand concentrated to give a white solid which was dissolved in MeOH:DMSO(1 ml, 1:1, v/v) and further purified by MDAP (method B). Theappropriate fractions were basified to pH 6 with saturated sodiumbicarbonate solution and extracted with ethyl acetate (2×25 ml). Thecombined organics were dried and evaporated in vacuo to give a whitesolid which was further dried under nitrogen at 40° C. for 3 h to givethe title compound as a white solid (26 mg).

LCMS (Method A): Rt 0.53 mins, MH⁺ 513.

Method B

N-[2-(Methyloxy)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-pyridinyl]methanesulfonamide(101 g, 308 mmol),6-chloro-4-(5-{[(2R,6S)-2,6-dimethyl-4-morpholinyl]methyl}-1,3-oxazol-2-yl)-1-(phenylsulfonyl)-1H-indazole(83.3 g, 154 mmol) and sodium bicarbonate (38.8 g, 462 mmol) weresuspended in 1,4-dioxane (1840 ml) and water (460 ml) under nitrogen andheated to 80° C.Chloro[2′-(dimethylamino)-2-biphenylyl]palladium-1(1R,4S)-bicyclo[2.2.1]hept-2-yl[(1S,4R)-bicyclo[2.2.1]hept-2-yl]phosphane(8.63 g, 15.40 mmol) was added and the mixture stirred overnight at 80°C.

The reaction mixture was cooled to 45° C. sodium hydroxide 2M aq. (770ml, 1540 mmol) added and the reaction heated to 45° C. for 4 hours. Themixture was cooled to RT and diluted with water (610 mL).Dichloromethane (920 mL) was added, and the mixture was filtered twicethrough Celite (washed with 200 mL 1,4-dioxane/DCM 2:1 each time). Thephases were separated, and aqueous washed with 1,4-dioxane/DCM 2:1 (500mL). The aqueous phase was neutralised with hydrochloric acid to pH ˜7and extracted with 1,4-dioxane/DCM 2:1 (1 L), then 1,4 dioxane/DCM 1:1(2×500 mL). The organics were washed with brine (500 mL), and filteredthrough Celite (washed with 200 mL 1,4 dioxane/DCM 2:1), and evaporatedto yield a dark black solid, which was purified in 4 batches:

Batch 1: 28 g was dissolved in Toluene/Ethanol/Ammonia 80:20:2 (100 mL)and purified by column chromatography (1.5 kg silica column), elutingwith Toluene/Ethanol/Ammonia 80:20:2 to give the title compound as anoff-white solid (14.78 g).

Batch 2: 30 g was dissolved in methanol and mixed with Fluorisil. Thesolvent was then removed by evaporation and the solid purified by columnchromatography (1.5 kg silica column, solid sample injection module),eluting with Toluene/Ethanol/Ammonia 80:20:2 to give the title compoundas an off-white solid (9.44 g).

Batch 3: 31 g was dissolved in Toluene/Ethanol/Ammonia 80:20:2 (100 mL)and purified by column chromatography (1.5 kg silica column), elutingwith Toluene/Ethanol/Ammonia 80:20:2 to give the title compound as anoff-white solid (17 g).

Batch 4: 29 g was dissolved in Toluene/Ethanol/Ammonia 80:20:2 (100 mL)and purified by column chromatography (1.5 kg silica column), elutingwith Toluene/Ethanol/Ammonia 80:20:2 to give the title compound as anoff-white solid (21 g).

The mixed fractions from the 4 columns were combined and evaporated toyield 19 g which was dissolved in 200 mL of Toluene/Ethanol/Ammonia80:20:2 (+ additional 4 ml of 0.88 NH3 to help solubility) then purifiedby column chromatography (1.5 kg silica column), eluting withToluene/Ethanol/Ammonia 80:20:2 to give the title compound as anoff-white solid (6.1 g).

All pure batches were combined (68 g) and recrystallised from ethanol(1200 mL). The suspension was heated to reflux and a solution formed.The resulting solution was then cooled to room temperature overnight.The resulting solid was then collected by filtration, washed sparinglywith ethanol and dried under vacuum to give the title compound as anoff-white solid (56 g). This material was recrystallised again fromethanol (1100 mL). The suspension was heated to reflux and a solutionformed. The resulting solution was then cooled to room temperatureovernight with stirring. The resulting solid was collected by filtrationand washed sparingly with ethanol. The solid was dried in vacuo at 60°C. for 5 hrs to give the title compound as an off-white solid (45.51 g).

LCMS (Method A): Rt 0.61 mins, MH⁺ 513.

The filtrate from the two recrystallisations was evaporated to yield ˜23g of a solid residue that was dissolved in 200 mL ofToluene/Ethanol/Ammonia 80:20:2 (+ additional 4 ml of 0.88 NH3 to helpsolubility) then purified by column chromatography (1.5 kg silicacolumn), eluting with Toluene/Ethanol/Ammonia 80:20:2 to give a furthercrop of the title compound as an off-white solid (18.5 g). This solidwas then recrystallised from ethanol (370 mL). The suspension was heatedto reflux then the resulting solution stirred for 20 mins before beingallowed to cool to room temperature naturally overnight. The solid wasthen dried in vacuo at 65° C. overnight to give the title compound as anoff-white solid (11.90 g).

LCMS (Method A): Rt 0.62 mins, MH⁺ 513.

Method C

10M Sodium hydroxide solution (0.70 ml) was added to a stirredsuspension ofN-[5-[4-(5-{[(2R,6S)-2,6-dimethyl-4-morpholinyl]methyl}-1,3-oxazol-2-yl)-1-(phenylsulfonyl)-1H-indazol-6-yl]-2-(methyloxy)-3-pyridinyl]methanesulfonamide(1.17 g) in water (5.8 ml). The resulting mixture was stirred at roomtemperature for 3.75 hours and was then washed with ethyl acetate (2×6ml). The layers were separated and the aqueous phase was acidified to pH6 with 2M hydrochloric acid (0.8 ml). The acidified aqueous layer wasextracted twice with ethyl acetate (11 ml then 5 ml). The combined ethylacetate extracts were dried by azeotropic distillation and diluted withfurther ethyl acetate (11 ml). The mixture was stirred at roomtemperature for 112 hours. The slurry was seeded and then stirred atroom temperature for 48 hours. The resultant suspension was filtered,washed with ethyl acetate (2×2 ml) and the solid dried under vacuum at4000 to give the title compound as a pale yellow solid (0.58 g).

LCMS (Method B): Rt 1.86 min, MH⁺ 513.

Method D

To a suspension ofN-[5-[4-(5-{[(2R,6S)-2,6-dimethyl-4-morpholinyl]methyl}-1,3-oxazol-2-yl)-1-(phenylsulfonyl)-1H-indazol-6-yl]-2-(methyloxy)-3-pyridinyl]methanesulfonamide(596.5 g, 0.91 mol) in water (3.8 L) is added 5M sodium hydroxide (715ml, 3.56 mol) over 20 mins at <25° C. The mixture is stirred at 20±3° C.for 2 h 45 min then washed with EtCN (3 L). The pH of the basic aqueousphase is adjusted to pH 6.6 using 2M hydrochloric acid (1.4 L),maintaining the temperature below 30° C. The mixture is then extractedwith MeTHF (2×4.8 L), and the combined MeTHF extracts are washed withwater (1.2 L). The mixture is concentrated to approx 2.4 L and EtOAc (3L) is added. This put and take distillation is repeated a further 3times. The mixture is adjusted to 60±3° C. and seeded twice (2×3 g) 35mins apart. The resultant is aged for 1 h 10 mins then cooled over 2 hto 20-25° C., and aged for a further 15 h 50 min. The slurry isfiltered, washed with EtOAc (2×1.2 L) and dried in vacuo at 45±5° C. forapprox 3 day to give the title compound.

Preparation of Polymorphs of Compound A Form (II)

Ethyl acetate (15 ml) was added toN-[5-[4-(5-{[(2R,6S)-2,6-dimethyl-4-morpholinyl]methyl}-1,3-oxazol-2-yl)-1H-indazol-6-yl]-2-(methyloxy)-3-pyridinyl]methanesulfonamide(2.1 g) and was stirred at ambient conditions overnight. The resultantslurry was filtered and dried under vacuum at 50° C. to give a new solidstate form (91% w/w).

¹H NMR (400 MHz, DMSO d6) d=13.49 (br s, 1H), 9.39 (s, 1H), 8.58 (s,1H), 8.42 (d, J=2.2 Hz, 1H), 7.99 (d, J=2.2 Hz, 1H), 7.93 (d, J=1.2 Hz,1H), 7.88 (s, 1H), 7.35 (s, 1H), 4.00 (s, 3H), 3.74 (s, 2H), 3.58 (m,2H), 3.11 (s, 3H), 2.80 (d, J=10.3 Hz, 2H), 1.78 (t, J=10.3 Hz, 2H),1.05 (d, J=6.4 Hz, 6H)

Form (III)

Methanol (4 ml) was added toN-[5-[4-(5-{[(2R,6S)-2,6-dimethyl-4-morpholinyl]methyl}-1,3-oxazol-2-yl)-1H-indazol-6-yl]-2-(methyloxy)-3-pyridinyl]methanesulfonamide(0.3 g) followed by fumaric acid (0.0764 g) in methanol (2 ml). Theresultant suspension was diluted further with methanol (3 ml) andstirred overnight at ambient conditions. The suspension was filtered,washed with methanol and air dried to give a new solid state form (64%w/w).

¹H NMR (400 MHz, DMSO d6) d=13.50 (br s, 1H), 9.39 (s, 1H), 8.58 (s,1H), 8.42 (d, J=2.2 Hz, 1H), 7.99 (d, J=2.2 Hz, 1H), 7.93 (d, J=1.2 Hz,1H), 7.88 (s, 1H), 7.35 (s, 1H), 4.00 (s, 3H), 3.74 (s, 2H), 3.58 (m,2H), 3.11 (s, 3H), 2.80 (d, J=10.3 Hz, 2H), 1.78 (t, J=10.5 Hz, 2H),1.05 (d, J=6.4 Hz, 6H)

Form (IV)

Tetrahydrofuran was saturated withN-[5-[4-(5-{[(2R,6S)-2,6-dimethyl-4-morpholinyl]methyl}-1,3-oxazol-2-yl)-1H-indazol-6-yl]-2-(methyloxy)-3-pyridinyl]methanesulfonamideat room temperature and heated. The suspension was cooled to roomtemperature and solids filtered, washed with THF and dried under vacuumat 30° C. to give a new solid state form.

¹H NMR (400 MHz, DMSO d6) d=13.50 (br s, 1H), 9.39 (s, 1H), 8.58 (s,1H), 8.41 (d, J=2.0 Hz, 1H), 7.98 (d, J=2.2 Hz, 1H), 7.93 (d, J=0.7 Hz,1H), 7.88 (s, 1H), 7.35 (s, 1H), 4.00 (s, 3H), 3.74 (s, 2H), 3.58 (m,2.4H), 3.11 (s, 3H), 2.80 (d, J=10.5 Hz, 2H), 1.78 (t, J=10.5 Hz, 2.4H),1.05 (d, J=6.1 Hz, 6H)

Sample contains 0.2 molar equivalents tetrahydrofuran

X-Ray Powder Diffraction (XRPD) for Forms (II) to (IV)

The data were acquired on a PANalytical X'Pert Pro powderdiffractometer, model PW30401/60 using an X'Celerator detector. Theacquisition conditions were: radiation: Cu Kα, generator tension: 40 kV,generator current: 45 mA, start angle: 2.0° 2θ, end angle: 40.0° 2θ,step size: 0.0167° 2θ, time per step: 31.75 seconds. The sample wasprepared by mounting a few milligrams of sample on a silicon wafer (zerobackground) plate, resulting in a thin layer of powder.

Form (III) was lightly ground with pestle and mortar to reduce preferredorientation.

Form (II)

The XRPD data are shown in FIG. 1.

Characteristic XRPD angles and d-spacings for the solid state form aresummarised in Table 1. Peak positions were measured using Highscoresoftware.

TABLE 1 2θ/° d-spacing/Å 4.6 19.1 9.2 9.6 11.4 7.8 12.1 7.3 12.7 7.013.7 6.5 14.0 6.3 16.0 5.5 17.1 5.2 17.9 5.0 18.5 4.8 18.8 4.7 22.3 4.020.8 4.3 23.8 3.7 25.9 3.4

Form (III)

The XRPD data are shown in FIG. 2.

Characteristic XRPD angles and d-spacings for the solid state form aresummarised in Table 2. Peak positions were measured using Highscoresoftware.

TABLE 2 2θ/° d-spacing/Å 6.7 13.2 8.2 10.8 8.8 10.0 9.7 9.1 11.1 8.012.6 7.0 13.6 6.5 14.4 6.1 17.0 5.2 17.7 5.0 18.8 4.7 20.9 4.2 21.3 4.222.8 3.9 24.4 3.6 25.3 3.5

Form (IV)

The XRPD data are shown in FIG. 3.

Characteristic XRPD angles and d-spacings for the solid state form aresummarised in Table 3. Peak positions were measured using Highscoresoftware.

TABLE 3 2θ/° d-spacing/Å 5.8 15.2 11.1 8.0 11.6 7.6 14.0 6.3 17.5 5.119.3 4.6 22.3 4.0 25.7 3.5

Preparation of Salts of Compound A Sodium Salt

Methanol (2 ml) was added toN-[5-[4-(5-{[(2R,6S)-2,6-dimethyl-4-morpholinyl]methyl}-1,3-oxazol-2-yl)-1H-indazol-6-yl]-2-(methyloxy)-3-pyridinyl]methanesulfonamide(0.3 g) followed by aqueous sodium hydroxide (0.129 ml) to give asolution. Tert-butylmethylether (4 ml) was added to the solutionfollowed by seed crystals of the sodium salt and this suspension wasstirred overnight at ambient conditions. The suspension was filtered,washed with tert-butylmethylether (2 ml) and air dried to give thesodium salt (0.2312 g) as a hydrate.

NMR: Consistent with salt formation

¹H NMR (400 MHz, DMSO d6) d=13.35 (br s, 1H), 8.53 (s, 1H), 7.90 (d,J=1.2 Hz, 1H), 7.73 (s, 1H), 7.65 (d, J=2.5 Hz, 1H), 7.62 (d, J=2.2 Hz,1H), 7.33 (s, 1H), 4.00 (s, 3H), 3.80 (s, 3H), 3.59 (m, 2H). 2.83 (d,J=10.3, 2H), 2.61 (s, 3H), 1.78 (t, J=10.5 Hz, 2H), 1.05 (d, J=6.1 Hz,6H)

Tosylate Salt

A solution ofN-[5-[4-(5-{[(2R,6S)-2,6-dimethyl-4-morpholinyl]methyl}-1,3-oxazol-2-yl)-1H-indazol-6-yl]-2-(methyloxy)-3-pyridinyl]methanesulfonamide(0.3 g) in tetrahydrofuran (3 ml) was added to p-toluenesulfonic acid(0.1224 g) to give initially a solution. A suspension formed on stirringand was diluted with tetrahydrofuran (2 ml) and stirred overnight atambient conditions. The suspension was filtered, washed withtetrahydrofuran (2 ml) and air dried to give the tosylate (0.3759 g).

NMR: Consistent with mono tosylate formation

¹H NMR (400 MHz, DMSO d6) d=13.56 (br s, 1H), 10.38 (br s, 1H), 9.43 (s,1H), 8.69 (s, 1H), 8.43 (d, J=2.5 Hz, 1H), 8.03 (s, 1H), 7.99 (d, J=2.2Hz, 1H), 7.96 (s, 1H), 7.69 (s, 1H), 7.46 (d, J=7.8 Hz, 2H), 7.11 (d,J=7.8 Hz, 2H), 4.69 (br s, 2H), 4.00 (s, 3H), 3.80 (br s, 2H), 3.50 (brs, 2H), 3.11 (s, 3H), 2.80 (br s, 2H), 2.28 (s, 3H), 1.05 (d, J=6.1 Hz,6H) Sample contains 0.5 molar equivalents tetrahydrofuran NMR signals3.60 (m, 2H), 1.76 (m, 2H)

Maleate Salt

Methanol (4 ml) was added toN-[5-[4-(5-{[(2R,6S)-2,6-dimethyl-4-morpholinyl]methyl}-1,3-oxazol-2-yl)-1H-indazol-6-yl-2-(methyloxy)-3-pyridinyl]methanesulfonamide(0.3 g) followed by maleic acid (0.0749 g) in methanol (2 ml). Thesolution was allowed to crystallise overnight at ambient conditions. Theresultant suspension was filtered, washed with methanol (1 ml) and airdried to give the maleate (0.1441 g).

NMR: Consistent with mono maleate formation

¹H NMR (400 MHz, DMSO d6) d=13.53 (br s, 1H), 9.41 (s, 1H), 8.63 (s,1H), 8.42 (d, J=2.4 Hz, 1H), 7.99 (d, J=2.4 Hz, 1H), 7.98 (d, J=1.2 Hz,1H), 7.92 (s, 1H), 7.51 (s, 1H), 6.16 (s, 2H), 4.16 (br s, 2H), 4.00 (s,3H), 3.69 (br s, 2H)*, 3.11 (s+br s, 3H+2H), 2.22 (br s, 2H), 1.10 (d,J=6.4 Hz, 6H) *Partial increase in integral due to overlap with broadHOD peak

Hemi Pamoate Salt

Tetrahydrofuran (1 ml) was added to pamoic acid (0.0759 g) to give asuspension. This suspension was added toN-[5-[4-(5-{[(2R,6S)-2,6-dimethyl-4-morpholinyl]methyl}-1,3-oxazol-2-yl)-1-indazol-6-yl]-2-(methyloxy)-3-pyridinyl]methanesulfonamide(0.2 g). Further tetrahydrofuran (7 ml) and water (12 ml) were addedbefore the solution was reduced in volume by ca. 10% under a nitrogenflow. The resultant suspension was sonicated and stirred at ambientconditions overnight. The suspension was filtered, washed with water anddried under vacuum at 50° C. to give the hemi pamoate (0.092 g)containing 5% w/w water.

NMR: Consistent with hemi pamoate formation

¹H NMR (400 MHz, DMSO d6) d=13.51 (br s: 1H), 9.40 (s, 1H), 8.60 (s,1H), 8.42 (m, 2H), 8.13 (d, J=8.8 Hz, 1H), 7.99 (d, J=2.2 Hz, 1H), 7.95(s, 1H), 7.90 (s, 1H), 7.85 (d, J=8.0 Hz, 1H), 7.42 (s, 1H), 7.33 (t,J=7.3 Hz, 1H), 7.18 (t, J=7.1 Hz, 1H), 4.78 (s, 1H), 4.00 (s, 3H), 3.92(br s, 2H), 3.63 (m, 2H), 3.11 (s, 3H), 2.95 (d, J=11.0 Hz, 2H), 1.97(m, 2H), 1.07 (d, J=6.4 Hz, 6H)

Hemi Naphthalenedisulfonate Salt

Isopropylacetate (12 ml) was added toN-[5-{[4-(5-{[(2R,6S)-2,6-dimethyl-4-morpholinyl]methyl}-1,3-oxazol-2-yl)-1H-indazol-6-yl]-2-(methyloxy)-3-pyridinyl]methanesulfonamide(0.2 g) followed by naphthalenedisulfonic acid (0.0703 g) inisopropylacetate (2 ml). The suspension was stirred at ambienttemperature for 9 days prior to filtration and dryed under vacuum at 40°C. for 3 hrs to give the hemi napthalenedisulfonate.

NMR Consistent with hemi naphthalenedisulfonate formation

¹H NMR (400 MHz, DMSO d6) d=13.56 (br s, 1H), 10.38 (br s, 1H), 9.42 (s,1-t), 8.85 (d, J=8.8 Hz, 1H), 8.69 (s, 1H), 8.43 (d, J=2.5, 1H), 8.03(s, 1H), 7.99 (d, J=2.2 Hz, 1H), 7.96 (s, 1H), 7.93 (d, J=7.1 Hz, 1H),7.69 (br s, 1H), 7.40 (t, J=7.8 Hz, 1H), 4.68 (br s, 2H), 4.00 (s, 3H),3.80 (br s, 2H), 3.50 (br s, 2H), 3.11 (s, 3H), 2.80 (br s, 2H), 1.15(d, J=6.1 Hz, 6H)

Integrals at 4.68 and 2.80 are only at 1.6H not the expected 2H

Extra peaks due to ca. 0.1 eq isopropylacetate.

Raman: Not consistent with freebase forms known

Mesitylenesulfonate Salt

A solution of mesitylenesulfonic acid dihydrate (0.0698 g, 0.295 mmol,1.0 eq) in tetrahydrofuran (0.5 ml) was added toN-[5-[4-(5-{[(2R,6S)-2,6-dimethyl-4-morpholinyl]methyl}-1,3-oxazol-2-yl)-1H-indazol-6-yl]-2-(methyloxy)-3-pyridinyl]methanesulfonamide(0.1505 g, 0.294 mmol) and sonicated to give a clear solution. Afterstirring at ambient temperature for ca. 2 mins the solution had formed avery thick suspension. This was held at ambient temperature overnight.The solids were collected by filtration and washed with tetrahydrofuran(1-2 ml) before being dried in vacuo at 50° C. overnight to give themesitylenesulfonate salt (0.1399 g, 66.8% th).

NMR: consistent with salt formation

NMR (400 MHz, DMSO d6) d=13.56 (s, 1H), 10.39 (bs, 1H), 9.42 (s, 1H),8.69 (s, 1H), 8.43 (d, J=2.2 Hz, 1H), 8.03 (s, 1H), 7.99 (d, J=2.2 Hz,1H), 7.96 (s, 1H), 7.69 (s, 1H), 6.73 (s, 2H), 4.69 (bs, 2H), 4.01 (s,3H), 3.81 (bs, 2H), 3.49 (bs, 4H), 3.11 (s, 3H), 2.79 (bs, 2H), 2.16 (s,3H), 1.15 (d, J=6.1 Hz, 6H).

Two methyl groups from mesitylenesulfonic acid are not seen as theyoverlap with resonance from d₅H-DMSO.

Hemi Biphenyldisulfonate

A solution of biphenyldisulfonic acid (0.0465 g, 0.148 mmol, 0.5 eq) intetrahydrofuran (0.2 ml) and water (0.2 ml) was added toN-[5-[4-(5-{[(2R,6S)-2,6-dimethyl-4-morpholinyl]methyl}-1,3-oxazol-2-yl)-1H-indazol-6-yl]-2-(methyloxy)-3-pyridinyl]methanesulfonamide(0.1506 g, 0.294 mmol) and sonicated to give a solution which wasstirred at ambient temperature overnight. After this time the solutionset solid due to a precipitate. These solids were collected byfiltration and washed with tetrahydrofuran (1-2 ml) before being driedin vacuo at 50° C. overnight to give the hemi-biphenyldisulfonate salt(0.117 g, 59.5% th)

NMR: consistent with salt formation

NMR (400 MHz, DMSO d6) d=13.55 (s, 1H), 10.37 (bs, 1H), 9.42 (s, 1H),8.69 (s, 1H), 8.43 (d, J=2.2 Hz, 1H), 8.03 (s, 1H), 7.99 (d, J=2.2 Hz,1H), 7.96 (s, 1H), 7.66 (s+d, J=8.1 Hz, H+2H), 7.61 (d, J=8.3 Hz, 2H),4.69 (bs, 2H), 4.01 (s, 3H), 3.81 (bs, 2H), 3.50 (bs, 4H), 3.11 (s, 3H),2.79 (bs, 2H), 1.16 (d, J=6.1 Hz, 6H).

2-Naphthalenesulfonate (napsylate)

N-5-[4-(5-{[(2R,6S)-2,6-Dimethyl-4-morpholinyl]methyl}-1,3-oxazol-2-yl)-1H-indazol-6-yl]-2-(methyloxy)-3-pyridinyl]methanesulfonamide(0.200 g, 0.390 mmol) was dissolved in tetrahydrofuran (3.2 ml) andwater (0.8 ml). Separately, 2-naphthalenesulfonic acid (0.081 mg, 0.390mmol, 1.0 eq) was dissolved in tetrahydrofuran (0.8 ml) and added to theN-[5-[4-(5-{[(2R,6S)-2,6-dimethyl-4-morpholinyl]methyl}-1,3-oxazol-2-yl)-1H-indazol-6-yl]-2-(methyloxy)-3-pyridinyl]methanesulfonamidesolution. This was seeded with a previous napsylate salt, however theseseeds dissolved. The solution was allowed to evaporate at ambienttemperature for 2 days. The white solid formed was triturated in waterand sonicated before being filtered and washed with water. The dampsolids were dried further in vacuo at 40-50° C. for 5 days to give thenapsylate salt (254.8 mg, 91% th).

NMR: consistent with salt formation

NMR (400 MHz, DMSO d6) d=13.56 (s, 1H), 10.38 (bs, 1H), 9.42 (s, 1H),8.69 (s, 1H), 8.43 (d, J=2.2 Hz, 1H), 8.15 (s, 1H), 8.03 (s, 1H), 8.00(d, J=2.0 Hz, 1H), 7.96 (m, 2H), 7.86 (m, 2H), 7.71 (m, 2H), 7.53 (m,2H), 4.68 (bs, 2H), 4.01 (s, 3H), 3.79 (bs, 2H), 3.50 (bs, 2H), 3.11 (s,3H), 2.78 (bs, 2H), 1.14 (d, J=6.1 Hz, 6H).

NMR also shows some unidentified low level impurities and residualtetrahydrofuran (0.1 molar equivalents).

Hemi Cinnamate Method A

N-[5-[4-(5-[4({[(2R,6S)-2,6-Dimethyl-4-morpholinyl]methyl}-1,3-oxazol-2-yl)-1H-indazol-6-yl]-2-(methyloxy)-3-pyridinyl]methanesulfonamide(0.02505 g, 0.049 mmol) was treated with trans-cinnamic acid (0.01453 g,0.098 mmol, 2.0 eq) in methanol (0.5 ml). This was heated with a hot airgun until dissolution occurred then allowed to cool to room temperature.

Solids precipitated on returning to room temperature and were allowed tostir overnight. The solids were filtered and solvent removed by pullingvacuum through the cake to give the salt.

Method B

N-[5-[4-(5-{[(2R,6S)-2,6-Dimethyl-4-morpholinyl]methyl}-1,3-oxazol-2-yl)-1H-indazol-6-yl]-2-(methyloxy)-3-pyridinyl]methanesulfonamide(80 g, 0.156 mol) and trans-cinnamic acid (58.66 g, 0.396 mol, 2.5 eq)were dissolved in methanol (3.2 L) by heating to 65° C. The solution wascooled to 60° C. and seeded withN-[5-[4-(5-{[(2R,6S)-2,6-dimethyl-4-morpholinyl]methyl}-1,3-oxazol-2-yl)-1H-indazol-6-yl]-2-(methyloxy)-3-pyridinyl]methanesulfonamidehemi-cinnamate (0.0802 g), these dissolved so the solution was cooledfurther to 50° C. and reseeded withN-[5-[4-(5-{[(2R,6S)-2,6-dimethyl-4-morpholinyl]methyl}-1,3-oxazol-2-yl)-1-indazol-6-yl]-2-(methyloxy)-3-pyridinyl]methanesulfonamidehemi-cinnamate. This was stirred for 1 hr at 50° C. and then cooled at˜0.167° C./min to 20° C. After 2 hrs a sample was taken and proved to beForm 3 by Raman analysis. The slurry was heated back to reflux to give asolution and extra methanol (100 ml) was added to make up for solventlosses incurred during the extended high temperature process. Thesolution was cooled to 25° C. and sample taken which was seeded withN-[5-[4-(5-{[(2R,6S)-2,6-dimethyl-4-morpholinyl]methyl}-1,3-oxazol-2-yl)-1H-indazol-6-yl]-2-(methyloxy)-3-pyridinyl]methanesulfonamidehemi-cinnamate. This seeded sample was aged for 20 mins and then used toseed the bulk solution. This was allowed to stir at 25° C. for 16 hrs.The slurry was filtered and sucked dry before being dried in vacuo at50° C. to give the salt (75.4 g, 82.5% th).

NMR: consistent with salt formation

NMR (400 MHz, DMSO d6) d=13.49 (bs, 1H), 9.40 (bs, 1H), 8.58 (s, 1H),8.42 (d, J=2.5 Hz, 1H), 7.99 (d, J=2.2 Hz, 1H), 7.94 (s, 1H), 7.88 (s,1H), 7.68 (m, 1H), 7.57 (d, J=16.1 Hz, 0.5H), 7.42 (m, 1.5H), 7.35 (s,1H), 6.55 (d, J=15.9 Hz, 0.5H), 4.01 (s, 3H), 3.74 (s, 2H), 3.58 (m,2H), 3.12 (s, 3H), 2.80 (d, J=10.5, 2H), 1.78 (t, J=10.5, 2H), 1.05 (d,J=6.1 Hz, 6H).

NMR also shows residual methanol (signal 3.18 ppm) at <0.1 molarequivalents.

Hemi Sebacate

A solution of sebacic acid (118.6 mg, 0.586 mmol, 2.0 eq) in THF (2 ml)was made up and added toN-[5-[4-(5-{[(2R,6S)-2,6-dimethyl-4-morpholinyl]methyl}-1,3-oxazol-2-yl)-1H-indazol-6-yl]-2-(methyloxy)-3-pyridinyl]methanesulfonamide(150.6 mg, 0.294 mmol) and heated to give a clear solution. The solutionwas allowed to cool to room temperature with stirring and after 2 hrssolids were present. A further aliquot of THF was added at this pointand the suspension stirred overnight at ambient temperature. The solidswere isolated by filtration and dried in vacuo at 5° C. overnight togive the hemi-sebacate salt.

NMR: consistent with salt formation

NMR (400 MHz, DMSO d6) d=13.49 (s, 1H), 11.94 (bs, 1H), 10.38 (bs, 1H),9.38 (s, 1H), 8.58 (s, 1H), 8.42 (d, J=2.2 Hz, 1H), 7.99 (d, J=2.0 Hz,1H), 7.93 (s, 1H), 7.88 (s, 1H), 7.35 (s, 1H), 4.00 (s, 3H), 3.74 (s,2H), 3.11 (s, 3H), 2.80 (d, J=10.5, 2H), 2.18 (t, J=7.3 Hz, 2H), 1.48(t, J=6.8 Hz, 2H), 1.25 (s, 4H), 1.05 (d, J=6.1 Hz, 6H).

Sample contains 0.85 molar equivalents tetrahydrofuran—NMR signals 3.60ppm (m, 3.3H) and 1.76 ppm (m, 3.4H).

Hemi Pyromellitate

A solution of pyromellitic acid (0.0546 g, 0.215 mmol, 0.55 eq) was madeup in tetrahydrofuran (1 ml) and added toN-[5-[4-(5-{[(2R,6S)-2,6-dimethyl-4-morpholinyl]methyl}-1,3-oxazol-2-yl)-1H-indazol-6-yl]-2-(methyloxy)-3-pyridinyl]methanesulfonamide(0.1999 g, 0.390 mmol) followed by further tetrahydrofuran (1 ml). Thissuspension was sonicated at which point the solids changed physicalcharacter and set solid. A further aliquot of tetrahydrofuran (2 ml) wasadded and the solution was heated and sonicated, however dissolution wasnot observed. The suspension was allowed to cool and stir overnight atroom temperature. The solids were collected by filtration and washedwith tetrahydrofuran (2 ml) before drying in vacuo overnight at 50° C.to give the hemi-pyromellitate salt as a tetrahydrofuran solvate.

NMR: consistent with salt formation

NMR (400 MHz, DMSO d6) d=13.52 (s, 1H), 9.39 (s, 1H), 8.61 (s, 1H), 8.42(d, J=2.2 Hz, 1H), 8.20 (s, 1H), 7.99 (d, J=2.2 Hz, 1H), 7.96 (s, 1H),7.91 (s, 1H), 7.45 (s, 1H), 4.01 (s, 5H). 3.60 (m, 6H), 3.11 (s, 3H),3.02 (d, J=10.8 Hz, 2H), 2.06 (bs, 2H), 1.76 (m, 4H), 1.05 (d, J=6.1 Hz,6H).

Tetrahydrofuran signals are 3.60 ppm (m, 4H) and 1.76 ppm (M, 4H)corresponding to 1 molar equivalent.

Hemi Benzenediacrylate

1,4-Benzenediacrylic acid (0.0431 g, 0.197 mmol, 0.5 eq) was dissolvedin dimethylsulfoxide (0.5 min) with heating, this was added toN-[5-[4-(5-{[(2R,6S)-2,6-dimethyl-4-morpholinyl]methyl}-1,3-oxazol-2-yl)-1H-indazol-6-yl]-2-(methyloxy)-3-pyridinyl]methanesulfonamide(0.2003 g, 0.391 mmol) and heated to give a solution. Tetrahydrofuran (1ml) was added to the solution and it was then heated and sonicatedbefore being allowed to stir at room temperature overnight. The solidswere isolated by filtration and washed with tetrahydrofuran before beingdried in vacuo at 65° C. overnight to give the hemi-benzenediacrylatesalt (0.1385 g, 57% th).

NMR: consistent with salt formation

NMR (400 MHz, DMSO d6) d=13.49 (bs, 1H), 12.40 (bs, 1H), 9.38 (bs, 1H),8.58 (s, 1H), 8.42 (d, J=2.2 Hz, 1H), 7.99 (d, J=2.2 Hz, 1H), 7.93 (s,1H), 7.88 (s, 1H), 7.73 (s, 2H), 7.58 (d, J=16.1 Hz, 1H), 7.35 (s, 1H),6.62 (d, J=16.1 Hz, 1H), 4.00 (s, 3H), 3.74 (s, 2H), 3.11 (s, 3H), 2.80(d, J=10.5 Hz, 2H), 1.05 (d, J=6.4 Hz, 6H).

Tetrahydrofuran signals are 3.60 ppm (m, 2.7H) and 1.78 ppm (m, 2.7H)corresponding to 0.68 molar equivalent. Dimethylsulfoxide signal is 2.54ppm (s, 0.7H) corresponding to 0.12 molar equivalents.

What is claimed is:
 1. A polymorph (Form II) ofN-[5-[4-(5-{[(2R,6S)-2,6-dimethyl-4-morpholinyl]methyl}-1,3-oxazol-2-yl)-1H-indazol-6-yl]-2-(methyloxy)-3-pyridinyl]methanesulfonamidecharacterised in that it provides an XRPD pattern comprising peaks (°2θ)at about 4.6, about 9.2, about 11.4 and/or about 12.7.
 2. A polymorphaccording to claim 1 characterised in that it provides an XRPD patterncomprising peaks substantially as set out in Table
 1. 3. A polymorphaccording to claim 1 in that it provides an XRPD pattern substantiallyin accordance with FIG.
 1. 4-6. (canceled)
 7. A polymorph (Form IV) ofN-[5-[4-(5-{[(2R,6S)-2,6-dimethyl-4-morpholinyl]methyl}-1,3-oxazol-2-yl)-1H-indazol-6-yl]-2-(methyloxy)-3-pyridinyl]methanesulfonamidecharacterised in that it provides an XRPD pattern comprising peaks (°2θ)at about 5.8, and/or about 11.6.
 8. A polymorph according to claim 8characterised in that it provides an XRPD pattern comprising peakssubstantially as set out in Table
 3. 9. A polymorph according to claim 7characterised in that it provides an XRPD pattern substantially inaccordance with FIG.
 3. 10. A salt ofN-[5-[4-(5-{[(2R,6S)-2,6-dimethyl-4-morpholinyl]methyl}-1,3-oxazol-2-yl)-1H-indazol-6-yl]-2-(methyloxy)-3-pyridinyl]methanesulfonamidewhich is the sodium, tosylate, maleate, hemi pamoate, heminaphthalenedisulfonate, mesitylenesulfonate, hemi biphenyldisulfonate,2-naphthalenesulfonate (napsylate), hemi cinnamate, hemi sebacate, hemipyromellitate or hemi benzenediacrylate salt.
 11. A pharmaceuticalcomposition comprising a polymorph or salt as defined in claim 1 and oneor more pharmaceutically acceptable excipients. 12-14. (canceled)
 15. Amethod of treating a disorder mediated by inappropriate PI3-kinaseactivity comprising administering a safe and effective amount of apolymorph or salt as defined in claim 1 to a patient in need thereof.